U.S. patent number 6,166,173 [Application Number 09/053,649] was granted by the patent office on 2000-12-26 for biodegradable polymers chain-extended by phosphates, compositions, articles and methods for making and using the same.
This patent grant is currently assigned to Guilford Pharmaceuticals Inc., Johns Hopkins University. Invention is credited to James P. English, Kam W. Leong, Hai-Quan Mao, Zhong Zhao.
United States Patent |
6,166,173 |
Mao , et al. |
December 26, 2000 |
Biodegradable polymers chain-extended by phosphates, compositions,
articles and methods for making and using the same
Abstract
Biodegradable polymers are described comprising the recurring
monomeric units shown in formula I or II: wherein X is --O-- or
--NR'--, where R' is H or alkyl; L is a branched or straight chain
aliphatic group having from 1-20 carbon atoms; M.sub.1 and M.sub.2
are each independently (1) a branched or straight chain aliphatic
group having from 1-20 carbon atoms; or (2) a branched or straight
chain, oxy-, carboxy- or amino-aliphatic group having from 1-20
carbon atoms; Y is --O--, --S-- or --NR'--, where R' is H or alkyl;
R is H, alkyl, alkoxy, aryl, aryloxy, heterocyclic or
heterocycloxy; the molar ratio of x:y is about 1; the molar ratio
n:(x or y) is between about 200:1 and 1:200; and the molar ratio
q:r is between about 1:99 and 99:1; wherein said biodegradable
polymer is biocompatible before and upon biodegradat. Processes for
preparing the polymers, compositions containing the polymers and
biologically active substances, articles useful for implantation or
injection into the body fabricated from the compositions, and
methods for controllably releasing biologically active substances
using the polymers, are also described.
Inventors: |
Mao; Hai-Quan (Towson, MD),
Leong; Kam W. (Ellicott City, MD), Zhao; Zhong
(Baltimore, MD), English; James P. (Chelsea, AL) |
Assignee: |
Guilford Pharmaceuticals Inc.
(Baltimore, MD)
Johns Hopkins University (Baltimore, MD)
|
Family
ID: |
25261018 |
Appl.
No.: |
09/053,649 |
Filed: |
April 2, 1998 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
Issue Date |
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832217 |
Apr 3, 1997 |
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Current U.S.
Class: |
528/398; 424/426;
523/111; 525/538; 528/400; 528/352; 523/113; 424/78.37; 424/486;
623/924 |
Current CPC
Class: |
A61L
17/12 (20130101); C08G 63/6922 (20130101); C08G
63/912 (20130101); A61L 26/0019 (20130101); A61L
27/18 (20130101); A61K 9/1647 (20130101); A61K
9/0024 (20130101); A61L 26/0019 (20130101); C08L
85/02 (20130101); A61L 27/18 (20130101); C08L
85/02 (20130101); Y10S 623/924 (20130101) |
Current International
Class: |
A61L
17/12 (20060101); A61L 17/00 (20060101); A61L
27/00 (20060101); A61L 27/18 (20060101); A61L
26/00 (20060101); C08G 63/692 (20060101); C08G
63/00 (20060101); A61K 9/00 (20060101); A61K
9/16 (20060101); C08G 63/91 (20060101); C08G
079/04 (); A61K 031/80 () |
Field of
Search: |
;523/111,113
;424/78.37,426,486 ;528/352,400,398 ;623/1,12,16C ;525/538 |
References Cited
[Referenced By]
U.S. Patent Documents
Foreign Patent Documents
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193 019 |
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Sep 1986 |
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EP |
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0 386 757 |
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Dec 1990 |
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EP |
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Other References
Petula et al., "High-molecular-weight Poly(alkylene Phosphonate)s
by Condensation of Dialkylphosphonates with Diols", Makromol.
Chem., 191:3, 671-80 (1990). .
Heller et al., "Release of Norethindrone from Poly(Ortho Esters)",
Polymer Engineering Sci., 21:11, 727-31 (1981)..
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Primary Examiner: Merriam; Andrew E. C.
Parent Case Text
This application is a continuation-in-part application of U.S.
patent application Ser. No. 08/832.217, filed Apr. 3, 1997, now
abandoned the contents of which are incorporated herein in their
entirety.
Claims
We claim:
1. A biodegradable polymer comprising the recurring monomeric units
shown in formula I or II: ##STR17## wherein: X is --O-- or --NR'--,
where R' is H or alkyl;
M.sub.1 and M.sub.2 are each independently (1) a branched or
straight chain aliphatic group having from 1-20 carbon atoms; or
(2) a branched or straight chain, oxy-, carboxy- or amino-aliphatic
group having from 1-20 carbon atoms;
Y is --O--, --S-- or --NR'--;
L is a branched or straight chain aliphatic group having from 1-20
carbon atoms;
R is H, alkyl, alkoxy, aryl, aryloxy, heterocyclic or
heterocycloxy;
the molar ratio of x:y is about 1;
the molar ratio n:(x or y) is between about 200:1 and 1:200;
and
the molar ratio q:r is between about 1:99 and 99:1;
wherein said biodegradable polymer is biocompatible before and upon
biodegradation.
2. The polymer of claim 1 wherein each of M.sub.1 and L is a
branched or straight chain alkylene group.
3. The polymer of claim 1 wherein each of M.sub.1 and L has from 1
to 7 carbon atoms.
4. The polymer of claim 1 wherein M.sub.1 is an ethylene group or a
methyl-substituted methylene group, and L is an ethylene group.
5. The polymer of claim 1 wherein R is an alkyl group, an alkoxy
group, a phenyl group, a phenoxy group, or a heterocycloxy
group.
6. The polymer of claim 1 wherein R is an alkoxy group having from
1 to 7 carbon atoms.
7. The polymer of claim 1 wherein R is an ethoxy group.
8. The polymer of claim 1 wherein each of M.sub.1 and M.sub.2 is a
branched or straight chain alkylene group.
9. The polymer of claim 1 wherein at least one of M.sub.1 and
M.sub.2 is an alkylene or alkoxylene group having a formula
selected from the group consisting of --(CH.sub.2).sub.a --,
--(CH.sub.2).sub.a --O--, and --(CH.sub.2).sub.a
--O--(CH.sub.2).sub.b --, wherein each of a and b is 1-7.
10. The polymer of claim 1 wherein at least one of M.sub.1 and
M.sub.2 has the formula: --CHR.sup.2 --CO--O--CHR.sup.3 --, wherein
R.sup.2 and R.sup.3 are each independently H, alkyl, alkoxy, aryl,
aryloxy, heterocyclic or heterocycloxy.
11. The polymer of claim 1 wherein each of M.sub.1 and M.sub.2 has
from 1 to 7 carbon atoms.
12. The polymer of claim 1 wherein X is --O--.
13. The polymer of claim 1 wherein X is --NR'--.
14. The polymer of claim 1 wherein:
M.sub.1 and M.sub.2 are each an alkylene or alkoxylene group;
L is an alkylene group;
X is --O--; and
R is an alkoxy group.
15. The polymer of claim 1 wherein the molar ratio n:(x or y) is
between about 50:1 and 1:50.
16. The polymer of claim 1 wherein the molar ratio q:r is between
about 1:50 and 50:1.
17. The polymer of claim 1 wherein each of x and y is about 1 to
1,000.
18. The polymer of claim 1 wherein the molar ratio n:(x or y) is
between about 100:1 and 1:100.
19. The polymer of claim 1 wherein said polymer is prepared by melt
polymerization.
20. The polymer of claim 1 wherein said polymer comprises
additional biocompatible monomeric units.
21. The polymer of claim 1 wherein said polymer is soluble in at
least one of the solvents selected from the group consisting of
acetone, dimethylene chloride, chloroform, ethyl acetate, DMAC,
N-methyl pyrrolidone, dimethylformamide and dimethylsulfoxide.
22. A process for preparing a biodegradable polymer comprising the
recurring monomeric units of formula I or II: ##STR18## wherein: X
is --O-- or --NR'--, where R' is H or alkyl;
M.sub.1 and M.sub.2 are each independently (1) a branched or
straight chain aliphatic group having from 1-20 carbon atoms; or
(2) a branched or straight chain, oxy-, carboxy- or amino-aliphatic
group having from 1-20 carbon atoms;
Y is --O--, --S-- or --NR'--;
L is a branched or straight chain aliphatic group having from 1-20
carbon atoms;
R is H, alkyl, alkoxy, aryl, aryloxy, heterocyclic or
heterocycloxy;
the molar ratio of x:y is about 1;
the molar ratio n:(x or y) is between about 200:1 and 1:200;
and
the molar ratio q:r is between about 1:99 and 99:1;
wherein said biodegradable polymer is biocompatible before and upon
biodegradation; wherein said biodegradable polymer is biocompatible
before and upon biodegradation, said process comprising the steps
of:
(a) reacting at least one heterocyclic ring compound having formula
III, IV or V: ##STR19## wherein M.sub.1, M.sub.2 and X are as
defined above,
with an initiator having the formula:
wherein Y and L are as defined as above, to form a prepolymer of
formula VI or VII, shown below: ##STR20## wherein X, M.sub.1,
M.sub.2, Y, L, R, x, y, q and r are as defined above; and
(b) further reacting said prepolymer of formula III, IV or V with a
phosphorodihalidate of formula VIII: ##STR21## where "halo" is Br,
Cl or I; and R is as defined above, to form said polymer of formula
I or II.
23. The process of claim 22 wherein each of M.sub.1 and L is a
branched or straight chain alkylene group having from 1 to 7 carbon
atoms.
24. The process of claim 22 wherein M.sub.1 is an ethylene group or
a methyl-substituted methylene group, and L is an ethylene
group.
25. The process of claim 22 wherein R is an alkoxy group having
from 1 to 7 carbon atoms.
26. The process of claim 22 wherein R is an ethoxy group.
27. The process of claim 22 wherein each of M.sub.1 and M.sub.2 is
a branched or straight chain alkylene group.
28. The process of claim 22 wherein at least one of M.sub.1 and
M.sub.2 is an alkylene or alkoxylene group having a formula
selected from the group consisting of --(CH.sub.2).sub.a --,
--(CH.sub.2).sub.a --O--, and --(CH.sub.2).sub.a
--O--(CH.sub.2).sub.b --, wherein each of a and b is 1-7.
29. The process of claim 22 wherein at least one of M.sub.1 and
M.sub.2 has the formula: --CHR.sup.2 --CO--O--CHR.sup.3 --, wherein
R.sup.2 and R.sup.3 are each independently H, alkyl, alkoxy, aryl,
aryloxy, heterocyclic or heterocycloxy.
30. The process of claim 22 wherein each of M.sub.1 and M.sub.2 has
from 1 to 7 carbon atoms.
31. The process of claim 22 wherein X is --O--.
32. The process of claim 22 wherein X is --NR'--.
33. The process of claim 22 wherein:
M.sub.1 and M.sub.2 are each an alkylene or alkoxylene group;
L is an alkylene group;
X is --O--; and
R is an alkoxy group.
34. The process of claim 22 wherein the molar ratio n:(x or y) is
between about 50:1 and 1:50.
35. The process of claim 22 wherein the molar ratio q:r is between
about 1:50 and 50:1.
36. The process of claim 22 wherein each of x and y are about 1 to
1,000.
37. The process of claim 22 wherein the molar ratio n:(x or y) is
from about 100:1 to about 1:100.
38. The process of claim 22 wherein said reacting step (a) takes
place at a temperature about 0 to about +235.degree. C.
39. The process of claim 22 wherein said reacting step (a) takes
place during a time between about 1 hour to seven days.
40. The process of claim 22 wherein, in said initiator, L is
substituted with one or more additional Y--H-- containing
substituents, wherein Y is as defined above.
41. The process of claim 22 wherein a catalyst is present during
said reacting step (a).
42. The process of claim 22 wherein, during the polymerization step
(b), an acid acceptor is present.
43. The process of claim 22 wherein said polymerization of step (b)
takes place at a temperature between about -40 and 150.degree.
C.
44. The process of claim 22 wherein said polymerization of step (b)
takes place during a time of about 30 minutes to 24 hours.
45. The process of claim 22 wherein said polymer of formula I or II
is purified by quenching a solution of said polymer with a
non-solvent or a partial solvent.
46. A biosorbable suture comprising the polymer of claim 1.
47. An orthopedic appliance, bone cement or bone wax for repairing
injuries to bone and connective tissue comprising the polymer of
claim 1.
48. A laminate for degradable or non-degradable fabrics comprising
the polymer of claim 1.
49. A coating for an implantable device comprising the polymer of
claim 1.
50. A biodegradable polymer composition comprising:
(a) at least one biologically active substance and
(b) a polymer having the recurring monomeric units shown in formula
I or II: ##STR22## wherein: X is --O-- or --NR'--, where R' is H or
alkyl;
M.sub.1 and M.sub.2 are each independently (1) a branched or
straight chain aliphatic group having from 1-20 carbon atoms; or
(2) a branched or straight chain, oxy-, carboxy- or amino-aliphatic
group having from 1-20 carbon atoms;
Y is --O--, --S-- or --NR'--;
L is a branched or straight chain aliphatic group having from 1-20
carbon atoms;
R is H, alkyl, alkoxy, aryl, aryloxy, heterocyclic or
heterocycloxy;
the molar ratio of x:y is about 1;
the molar ratio n:(x or y) is between about 200:1 and 1:200;
and
the molar ratio q:r is between about 1:99 and 99:1;
wherein said biodegradable polymer is biocompatible before and upon
biodegradation.
51. The polymer composition of claim 50 wherein each of M.sub.1 and
L is a branched or straight chain alkylene group.
52. The polymer composition of claim 50 wherein M.sub.1 is an
ethylene group or a methyl-substituted methylene group, and L is an
ethylene group.
53. The polymer composition of claim 50 wherein R is an alkyl
group, an alkoxy group, a phenyl group, a phenoxy group, or a
heterocycloxy group.
54. The polymer composition of claim 50 wherein R is an alkoxy
group.
55. The polymer composition of claim 50 wherein each of M.sub.1 and
M.sub.2 is a branched or straight chain alkylene group.
56. The polymer composition of claim 50 wherein at least one of
M.sub.1 and M.sub.1 is an alkylene or alkoxylene group having a
formula selected from the group consisting of --(CH.sub.2).sub.a
--, --(CH.sub.2).sub.a --O--, and --(CH.sub.2).sub.a
--O--(CH.sub.2).sub.b --, wherein each of a and b is 1-7.
57. The polymer compositions of claim 50 wherein at least one of
M.sub.1 and M.sub.2 has the formula: --CHR.sup.2 --CO--O--CHR.sup.3
--, wherein R.sup.2 and R.sup.3 are each independently H, alkyl,
alkoxy, aryl, aryloxy, heterocyclic or heterocycloxy.
58. The polymer compositions of claim 50 wherein each of M.sub.1
and M.sub.2 has from 1 to 7 carbon atoms.
59. The polymer compositions of claim 50 wherein X is --O--.
60. The polymer compositions of claim 50 wherein X is --NR'--.
61. The polymer compositions of claim 50 wherein:
M.sub.1 and M.sub.2 are each an alkylene or alkoxylene group;
L is an alkylene group;
X is --O--; and
R is an alkoxy group.
62. The polymer composition of claim 50 wherein the molar ratio n:
(x or y) is between about 50:1 and 1:50.
63. The polymer composition of claim 50 wherein the molar ratio q:r
is between about 1:50 and 50:1.
64. The polymer composition of claim 50 wherein each of x and y is
about 1 to 1,000.
65. The polymer composition of claim 50 wherein the ratio n:(x or
y) is from about 100:1 to about 1:100.
66. The polymer composition of claim 50 wherein said polymer is
prepared by melt polymerization.
67. The polymer composition of claim 50 wherein said polymer
comprises additional biocompatible monomeric units.
68. The polymer composition of claim 50 wherein said polymer is
soluble in at least one of the solvents selected from the group
consisting of acetone, dimethylene chloride, chloroform, ethyl
acetate, DMAC, N-methyl pyrrolidone, dimethylformamide and
dimethylsulfoxide.
69. The polymer composition of claim 50 wherein said biologically
active substance is selected from the group consisting of
polysaccharides, growth factors, hormones, anti-angiogenesis
factors, interferons or cytokines, and pro-drugs of these
substances.
70. The polymer composition of claim 50 wherein said biologically
active substance is a therapeutic drug or pro-drug.
71. The polymer composition of claim 70 wherein said drug is
selected from the group consisting of anti-neoplastic neoplastic
agents, antibiotics, anti-virals, anti-fungals,
anti-inflammatories, and anticoagulants.
72. The polymer composition of claim 71 wherein the anti-neoplastic
agent is paclitaxel.
73. The polymer composition of claim 50 wherein said biologically
active substance and said polymer form a homogeneous matrix.
74. The polymer composition of claim 50 wherein said polymer is
characterized by a release rate of the biologically active
substance in vivo controlled at least partially as a function of
hydrolysis of the phosphoester bond of the polymer during
biodegradation.
75. An article useful for implantation, injection, or otherwise
being placed totally or partially within the body, said article
comprising a biodegradable polymer composition comprising:
(a) at least one biologically active substance and
(b) a polymer having the recurring monomeric units shown in formula
I or II: ##STR23## wherein: X is --O-- or --NR'--, where R' is H or
alkyl;
M.sub.1 and M.sub.2 are each independently (1) a branched or
straight chain aliphatic group having from 1-20 carbon atoms; or
(2) a branched or straight chain, oxy-, carboxy- or amino-aliphatic
group having from 1-20 carbon atoms;
Y is --O--, --S-- or --NR'--;
L is a branched or straight chain aliphatic group having from 1-20
carbon atoms;
R is H, alkyl, alkoxy, aryl, aryloxy, heterocyclic or
heterocycloxy;
the molar ratio of x:y is about 1;
the molar ratio n:(x or y) is between about 200:1 and 1:200;
and
the molar ratio q:r is between about 1:99 and 99:1;
wherein said biodegradable polymer is biocompatible before and upon
biodegradation.
76. The article of claim 75 wherein each of M.sub.1 and L is a
branched or straight chain alkylene group.
77. The article of claim 75 wherein each of M.sub.1 and L has from
1 to 7 carbon atoms.
78. The article of claim 75 wherein R is an alkyl group, an alkoxy
group, a phenyl group, a phenoxy group, or a heterocycloxy
group.
79. The article of claim 75 wherein R is an alkoxy group.
80. The article of claim 75 wherein each of M.sub.1 and M.sub.2 is
a branched or straight chain alkylene group.
81. The article of claim 75 wherein at least one of M.sub.1 and
M.sub.2 is an alkylene or alkoxylene group having a formula
selected from the group consisting of --(CH.sub.2).sub.a --,
--(CH.sub.2).sub.a --O--, and --(CH.sub.2).sub.a
--O--(CH.sub.2).sub.b --, wherein each of a and b is 1-7.
82. The article of claim 75 wherein at least one of M.sub.1 and
M.sub.2 has the formula: --CHR.sup.2 --CO--O--CHR.sup.3 --, wherein
R.sup.2 and R.sup.3 are each independently H, alkyl, alkoxy, aryl,
aryloxy, heterocyclic or heterocycloxy.
83. The article of claim 75 wherein each of M.sub.1 and M.sub.2 has
from 1 to 7 carbon atoms.
84. The article of claim 75 wherein X is --O--.
85. The article of claim 75 wherein X is --NR'--.
86. The article of claim 75 wherein:
M.sub.1 and M.sub.2 are each an alkylene or alkoxylene group;
L is an alkylene group;
X is --O--; and
R is an alkoxy group.
87. The article of claim 75 wherein the molar ratio n:(x or y) is
between about 50:1 and 1:50.
88. The article of claim 75 wherein the molar ratio q:r is between
about 1:50 and 50:1.
89. The polymer composition of claim 75 wherein each of x and y is
about 1 to 1,000.
90. The article of claim 75 wherein the molar ratio n:(x or y) is
from about 100:1 to about 1:100.
91. The article of claim 75 wherein said polymer is prepared by
melt polymerization.
92. The article of claim 75 wherein said polymer comprises
additional biocompatible monomeric units.
93. The article of claim 75 wherein said polymer is soluble in at
least one of the solvents selected from the group consisting of
acetone, dimethylene chloride, chloroform, ethyl acetate, DMAC,
N-methyl pyrrolidone, dimethylformamide and dimethylsulfoxide.
94. The article of claim 75 wherein said biologically active
substance is selected from the group consisting of polysaccharides,
growth factors, hormones, anti-angiogenesis factors, interferons or
cytokines, and pro-drugs of these substances.
95. The article of claim 75 wherein said biologically active
substance is a therapeutic drug or pro-drug.
96. The article of claim 75 wherein said biologically active
substance is selected from the group consisting of anti-neoplastic
agents, antibiotics, anti-virals, anti-fungals,
anti-inflammatories, anticoagulants, and pro-drugs of these
substances.
97. The article of claim 75 wherein at least one biologically
active substance is paclitaxel.
98. The article of claim 75 wherein said biologically active
substance and said polymer form a homogeneous matrix.
99. The article of claim 75 wherein said biologically active
substance is encapsulated within said polymer.
100. The article of claim 75 wherein said polymer is characterized
by a release rate of the biologically active substance in vivo
controlled at least partially as a function of hydrolysis of the
phosphoester bond of the polymer upon biodegradation.
101. The article of claim 75 wherein said article is adapted for
implantation or injection into the body of an animal.
102. The article of claim 75 wherein said article is a
microsphere.
103. The article of claim 75 wherein said article results in
minimal tissue irritation when implanted or injected into
vasculated tissue.
104. The article of claim 75 wherein said article is in the form of
a laminate for degradable fabric.
105. The article of claim 75 wherein said article is in the form of
a biosorbable suture, a material for repairing bone injuries, or a
coating on an implant device.
106. A method for the controlled release of a biologically active
substance comprising the steps of:
(a) combining the biologically active substance with a
biodegradable polymer having the recurring monomeric units shown in
formula I or II: ##STR24## wherein: X is --O-- or --NR'--, where R'
is H or alkyl;
M.sub.1 and M.sub.2 are each independently (1) a branched or
straight chain aliphatic group having from 1-20 carbon atoms; or
(2) a branched or straight chain, oxy-, carboxy- or amino-aliphatic
group having from 1-20 carbon atoms;
Y is --O--, --S-- or --NR'--;
L is a branched or straight chain aliphatic group having from 1-20
carbon atoms;
R is H, alkyl, alkoxy, aryl, aryloxy, heterocyclic or
heterocycloxy;
the molar ratio of x:y is about 1;
the molar ratio n:(x or y) is between about 200:1 and 1:200;
and
the molar ratio q:r is between about 1:99 and 99:1;
wherein said biodegradable polymer is biocompatible before and upon
biodegradation, to form an admixture;
(b) forming said admixture into a shaped, solid article or
microsphere; and
(c) implanting or injecting said solid article or microsphere in
vivo at a preselected site, such that the solid implanted or
injected matrix is in at least partial contact with a biological
fluid.
107. The method of claim 106 wherein each of R and L is a branched
or straight chain alkylene group.
108. The method of claim 106 wherein R' is an alkoxy group.
109. The method of claim 106 wherein each of M.sub.1 and M.sub.2 is
a branched or straight chain alkylene group.
110. The method of claim 106 wherein at least one of M.sub.1 and
M.sub.2 is an alkylene or alkoxylene group having a formula
selected from the group consisting of --(CH.sub.2).sub.a --,
--(CH.sub.2).sub.a --O--, and --(CH.sub.2).sub.a
--O--(CH.sub.2).sub.b --, wherein each of a and b is 1-7.
111. The method of claim 106 wherein at least one of M.sub.1 and
M.sub.2 has the formula: --CHR.sup.2 --CO--O--CHR.sup.3 --, wherein
R.sup.2 and R.sup.3 are each independently H, alkyl, alkoxy, aryl,
aryloxy, heterocyclic or heterocycloxy.
112. The method of claim 106 wherein each of M.sub.1 and M.sub.2
has from 1 to 7 carbon atoms.
113. The method of claim 106 wherein X is --O--.
114. The method of claim 106 wherein X is --NR'--.
115. The method of claim 106 wherein:
M.sub.1 and M.sub.2 are each an alkylene or alkoxylene group;
L is an alkylene group;
X is --O--; and
R is an alkoxy group.
116. The method of claim 106 wherein the molar ratio n:(x or y) is
between about 50:1 and 1:50.
117. The method of claim 106 wherein the molar ratio q:r is between
about 1:50 and 50:1.
118. The polymer composition of claim 106 wherein each of x and y
is about 1 to 1,000.
119. The method of claim 106 wherein the molar ratio n:(x or y) is
from about 100:1 to about 1:100.
120. The method of claim 106 wherein said polymer comprises
additional biocompatible monomeric units.
121. The method of claim 106 wherein said biologically active
substance is selected from the group consisting of polysaccharides,
growth factors, hormones, anti-angiogenesis factors and other
anti-neoplastic agents, interferons or cytokines, and pro-drugs of
these substances.
122. The method of claim 106 wherein said biologically active
substance is paclitaxel.
123. The method of claim 106 wherein said biologically active
substance is a therapeutic drug or pro-drug.
124. The method of claim 106 wherein said drug is selected from the
group consisting of chemotherapeutic agents, antibiotics,
anti-virals, anti-fungals, anti-inflammatories, and
anticoagulants.
125. The method of claim 106 wherein said biologically active
substance and said polymer form a homogeneous matrix.
126. The method of claim 106 further comprising encapsulating said
biologically active substance within said polymer.
127. The method of claim 106 wherein said polymer is characterized
by a release rate of the biologically active substance in vivo
controlled at least partly as a function of hydrolysis of the
phosphoester bond of the polymer upon degradation.
128. The method of claim 106 wherein said article is non-toxic and
results in minimal tissue irritation when implanted or injected
into vasculated tissue.
129. The method of claim 106 wherein said article is in the form of
microspheres.
130. The method of claim 106 wherein said article is in the form of
a laminate for degradable fabric.
131. The method of claim 106 wherein said polymer composition is
used as a coating for an implant.
132. The method of claim 106 wherein the polymer composition is
used as a barrier for adhesion prevention.
133. The method of claim 106 wherein said polymer composition is
fabricated as a tube for nerve generation.
134. The article of claim 75, wherein at least one biologically
active substance is an analgesic or anesthetic.
135. The article of claim 75, wherein at least one biologically
active substance is lidocaine.
136. The article of claim 75, wherein at least one biologically
active substance is a radiosensitizer.
137. The method of claim 106, wherein said biologically active
substance is an analgesic or anesthetic.
138. The method of claim 106, wherein said biologically active
substance is lidocaine.
139. The method of claim 106, wherein said biologically active
substance is a radio sensitizer.
140. The biodegradable polymer composition of claim 50, wherein
said biologically active substance is an analgesic or
anesthetic.
141. The biodegradable polymer composition of claim 50, wherein
said biologically active substance is lidocaine.
142. The biodegradable polymer composition of claim 50, wherein
said biologically active substance is a radiosensitizer.
143. The biodegradable polymer of claim 1, wherein X and Y are
O.
144. The biodegradable polymer of claim 1, wherein R is OCH.sub.2
CH.sub.3.
145. The biodegradable polymer of claim 1, wherein the polymer
corresponds to formula I, and wherein X and Y are O, M.sub.1 is a
substituted carboxylic acid ester group, L, x, y, and n are as
defined in claim 1, the recurring monomeric units comprise the
following formula ##STR25## wherein R.sub.5 is an alkoxy or alkyl
group, and R.sub.4 is H or a branched or straight chain aliphatic
group of 1 to 7 carbon atoms.
146. The biodegradable polymer of claim 145, wherein R.sub.4 is a
methyl group.
147. The biodegradable polymer of claim 145, wherein R.sub.5 is
OCH.sub.2 CH.sub.3.
148. The biodegradable polymer of claim 145, wherein R.sub.5 is
CH.sub.2 CH.sub.3.
149. The biodegradable polymer of claim 145, wherein L is a
branched or straight chain aliphatic group of 1 to 7 carbon
atoms.
150. The biodegradable polymer of claim 145, wherein R.sub.4 is a
methyl group and R.sub.5 is --OCH.sub.2 CH.sub.3.
151. The biodegradable polymer of claim 145, wherein R.sub.4 is a
methyl group and R.sub.5 is --CH.sub.2 CH.sub.3.
152. The biodegradable polymer of claim 150, wherein L is a
branched or straight chain aliphatic group of 1 to 7 carbon
atoms.
153. The biodegradable polymer of claim 151, wherein L is a
branched or straight chain aliphatic group of 1 to 7 carbon
atoms.
154. The biodegradable polymer of claim 150, wherein L is an
ethylene group.
155. The biodegradable polymer of claim 1, wherein the recurring
monomeric units comprise the following formula ##STR26## 156.
156. The process of claim 22, wherein X and Y are O.
157. The process of claim 22, wherein in step (a), a heterocyclic
ring compound of formula V is selected.
158. The process of claim 157, wherein M.sub.1 and M.sub.2 are the
same.
159. The process of claim 158, wherein M.sub.1 and M.sub.2 are
branched or straight chain aliphatic groups of 1 to 20 carbon
atoms.
160. The process of claim 159, wherein M.sub.1 and M.sub.2 are
methyl substituted methylene groups.
161. The process of claim 22, wherein O is selected for the Y group
of the initiator.
162. The process of claim 22, wherein the L group in the initiator
is a branched or straight chain aliphatic group of 1 to 7 carbon
atoms.
163. The process of claim 157, wherein the L group in the initiator
is a branched or straight chain aliphatic group of 1 to 7 carbon
atoms and wherein O is selected for the Y group of the
initiator.
164. The process of claim 158, wherein the L group in the initiator
is a branched or straight chain aliphatic group of 1 to 7 carbon
atoms and wherein O is selected for the Y group of the
initiator.
165. The process of claim 159, wherein the L group in the initiator
is a branched or straight chain aliphatic group of 1 to 7 carbon
atoms and wherein O is selected for the Y group of the
initiator.
166. The process of claim 22, wherein the R group of the formula
VIII phosphorodihalidate compound is an alkoxy group.
167. The process of claim 22, wherein the R group of the formula
VIII phosphorodihalidate compound is an --OCH.sub.2 CH.sub.3.
168. The process of claim 22, wherein the R group of the formula
VIII phosphorodihalidate compound is an --CH.sub.2 CH.sub.3.
169. The process of claim 163, wherein the R group of the formula
VIII phosphorodihalidate compound is an --OCH.sub.2 CH.sub.3.
170. The process of claim 163, wherein the R group of the formula
VIII phosphorodihalidate compound is an --CH.sub.2 CH.sub.3.
171. The process of claim 164, wherein the R group of the formula
VIII phosphorodihalidate compound is an --OCH.sub.2 CH.sub.3.
172. The process of claim 164, wherein the R group of the formula
VIII phosphorodihalidate compound is an --CH.sub.2 CH.sub.3.
173. The process of claim 165, wherein the R group of the formula
VIII phosphorodihalidate compound is an --OCH.sub.2 CH.sub.3.
174. The process of claim 165, wherein the R group of the formula
VIII phosphorodihalidate compound is an --CH.sub.2 CH.sub.3.
175. The process of claim 22, further comprising addition of a
biologically active substance to form an article, implant, or
device useful for implantation, injection, or otherwise being
placed totally or partially within the body.
176. The process of claim 156, further comprising addition of a
biologically active substance to form an article, implant, or
device useful for implantation, injection, or otherwise being
placed totally or partially within the body.
177. The process of claim 157, further comprising addition of a
biologically active substance to form an article, implant, or
device useful for implantation, injection, or otherwise being
placed totally or partially within the body.
178. The process of claim 158, further comprising addition of a
biologically active substance to form an article, implant, or
device useful for implantation, injection, or otherwise being
placed totally or partially within the body.
179. The process of claim 163, further comprising addition of a
biologically active substance to form an article, implant, or
device usefl for implantation, injection, or otherwise being placed
totally or partially within the body.
180. The process of claim 164, further comprising addition of a
biologically active substance to form an article, implant, or
device useful for implantation, injection, or otherwise being
placed totally or partially within the body.
181. The process of claim 165, further comprising addition of a
biologically active substance to form an article, implant, or
device useful for implantation, injection, or otherwise being
placed totally or partially within the body.
182. The process of claim 166, further comprising addition of a
biologically active substance to form an article, implant, or
device useful for implantation, injection, or otherwise being
placed totally or partially within the body.
183. The process of claim 167, further comprising addition of a
biologically active substance to form an article, implant, or
device useful for implantation, injection, or otherwise being
placed totally or partially within the body.
184. The process of claim 168, further comprising addition of a
biologically active substance to form an article, implant, or
device useful for implantation, injection, or otherwise being
placed totally or partially within the body.
185. The process of claim 169, further comprising addition of a
biologically active substance to form an article, implant, or
device useful for implantation, injection, or otherwise being
placed totally or partially within the body.
186. The process of claim 170, further comprising addition of a
biologically active substance to form an article, implant, or
device useful for implantation, injection, or otherwise being
placed totally or partially within the body.
187. The process of claim 171, further comprising addition of a
biologically active substance to form an article, implant, or
device useful for implantation, injection, or otherwise being
placed totally or partially within the body.
188. The process of claim 172, further comprising addition of a
biologically active substance to form an article, implant, or
device useful for implantation, injection, or otherwise being
placed totally or partially within the body.
189. The process of claim 173, further comprising addition of a
biologically active substance to form an article, implant, or
device useful for implantation, injection, or otherwise being
placed totally or partially within the body.
190. The process of claim 174, further comprising addition of a
biologically active substance to form an article, implant, or
device useful for implantation, injection, or otherwise being
placed totally or partially within the body.
191. The process of claim 22, wherein the recurring monomeric units
comprise the following formula
192. The process of claim 191, further comprising addition of a
biologically active substance to form an article, implant, or
device useful for implantation, injection, or otherwise being
placed totally or partially within the body.
193. The process of claim 191, wherein the biologically active
substance is selected from the group consisting of analgesics,
anesthetics, radiosensitizers, lidocaine, and paclitaxel.
194. The biodegradable polymer composition of claim 50, wherein X
and Y are O.
195. The biodegradable polymer composition of claim 50, wherein R
is --OCH.sub.2 CH.sub.3.
196. The biodegradable polymer composition of claim 50, wherein R
is --CH.sub.2 CH.sub.3.
197. The biodegradable polymer composition of claim 50, wherein the
polymer corresponds to formula I, and wherein X and Y are O,
M.sub.1 is a substituted carboxylic acid ester group, L, x, y, and
n are as defined in claim 1, the recurring monomeric units comprise
the following formula wherein R.sub.5 is an alkoxy or alkyl group,
and R.sub.4 is H or a branched or straight chain aliphatic group of
1 to 7 carbon atoms.
198. The biodegradable polymer composition of claim 197, wherein
R.sub.4 is a methyl group.
199. The biodegradable polymer composition of claim 197, wherein
R.sub.5 is --OCH.sub.2 CH.sub.3.
200. The biodegradable polymer composition of claim 197, wherein
R.sub.5 is --CH.sub.2 CH.sub.3.
201. The biodegradable polymer composition of claim 197, wherein L
is a branched or straight chain aliphatic group of 1 to 7 carbon
atoms.
202. The biodegradable polymer composition of claim 197, wherein
R.sub.4 is a methyl group and R.sub.5 is --OCH.sub.2 CH.sub.3.
203. The biodegradable polymer composition of claim 197, wherein
R.sub.4 is a methyl group and R.sub.5 is --CH.sub.2 CH.sub.3.
204. The biodegradable polymer composition of claim 202, wherein L
is a branched or straight chain aliphatic group of 1 to 7 carbon
atoms.
205. The biodegradable polymer composition of claim 203, wherein L
is a branched or straight chain aliphatic group of 1 to 7 carbon
atoms.
206. The biodegradable polymer composition of claim 204, wherein L
is an ethylene group.
207. The biodegradable polymer composition of claim 50, wherein the
recurring monomeric units comprise the following formula ##STR27##
208.
208. The biodegradable polymer composition of claim 197, wherein
the biologically active substance is selected from the group
consisting of analgesics, anesthetics, radiosensitizers, lidocaine,
and paclitaxel.
209. The biodegradable polymer composition of claim 198, wherein
the biologically active substance is selected from the group
consisting of analgesics, anesthetics, radiosensitizers, lidocaine,
and paclitaxel.
210. The biodegradable polymer composition of claim 199, wherein
the biologically active substance is selected from the group
consisting of analgesics, anesthetics, radiosensitizers, lidocaine,
and paclitaxel.
211. The biodegradable polymer composition of claim 200, wherein
the biologically active substance is selected from the group
consisting of analgesics, anesthetics, radiosensitizers, lidocaine,
and paclitaxel.
212. The biodegradable polymer composition of claim 201, wherein
the biologically active substance is selected from the group
consisting of analgesics, anesthetics, radiosensitizers, lidocaine,
and paclitaxel.
213. The biodegradable polymer composition of claim 202, wherein
the biologically active substance is selected from the group
consisting of analgesics, anesthetics, radiosensitizers, lidocaine,
and paclitaxel.
214. The biodegradable polymer composition of claim 203, wherein
the biologically active substance is selected from the group
consisting of analgesics, anesthetics, radiosensitizers, lidocaine,
and paclitaxel.
215. The biodegradable polymer composition of claim 204, wherein
the biologically active substance is selected from the group
consisting of analgesics, anesthetics, radiosensitizers, lidocaine,
and paclitaxel.
216. The biodegradable polymer composition of claim 205, wherein
the biologically active substance is selected from the group
consisting of analgesics, anesthetics, radiosensitizers, lidocaine,
and paclitaxel.
217. The biodegradable polymer composition of claim 206, wherein
the biologically active substance is selected from the group
consisting of analgesics, anesthetics, radiosensitizers, lidocaine,
and paclitaxel.
218. The biodegradable polymer composition of claim 207, wherein
the biologically active substance is selected from the group
consisting of analgesics, anesthetics, radiosensitizers, lidocaine,
and paclitaxel.
219. The article of claim 75, wherein X and Y are O.
220. The article of claim 219, wherein and R is --OCH.sub.2
CH.sub.3.
221. The article of claim 219, wherein and R is --CH.sub.2
CH.sub.3.
222. The article of claim 75, wherein the polymer corresponds to
formula I, and wherein X and Y are O, M.sub.1 is a substituted
carboxylic acid ester group, L, x, y, and n are as defined in claim
1, the recurring monomeric units comprise the following formula
wherein R.sub.5 is an alkoxy or alkyl group, and R.sub.4 is H or a
branched or straight chain aliphatic group of 1 to 7 carbon
atoms.
223. The article of claim 222, wherein R.sub.4 is a methyl
group.
224. The article of claim 222, wherein R.sub.5 is --OCH.sub.2
CH.sub.3.
225. The article of claim 222, wherein R.sub.5 is --CH.sub.2
CH.sub.3.
226. The article of claim 222, wherein L is a branched or straight
chain aliphatic group of 1 to 7 carbon atoms.
227. The article of claim 222, wherein R.sub.4 is a methyl group
and R.sub.5 is --OCH.sub.2 CH.sub.3.
228. The article of claim 222, wherein R.sub.4 is a methyl group
and R.sub.5 is --CH.sub.2 CH.sub.3.
229. The article of claim 223, wherein L is a branched or straight
chain aliphatic group of 1 to 7 carbon atoms.
230. The article of claim 224, wherein L is a branched or straight
chain aliphatic group of 1 to 7 carbon atoms.
231. The article of claim 225, wherein L is a branched or straight
chain aliphatic group of 1 to 7 carbon atoms.
232. The article of claim 227, wherein L is an ethylene group.
233. The article of claim 75, wherein the recurring monomeric units
comprise the following formula ##STR28## 234.
234. The article of claim 220, wherein the biologically active
substance is selected from the group consisting of analgesics,
anesthetics, radiosensitizers, lidocaine, and paclitaxel.
235. The article of claim 221, wherein the biologically active
substance is selected from the group consisting of analgesics,
anesthetics, radiosensitizers, lidocaine, and paclitaxel.
236. The article of claim 222, wherein the biologically active
substance is selected from the group consisting of analgesics,
anesthetics, radiosensitizers, lidocaine, and paclitaxel.
237. The article of claim 223, wherein the biologically active
substance is selected from the group consisting of analgesics,
anesthetics, radiosensitizers, lidocaine, and paclitaxel.
238. The article of claim 224, wherein the biologically active
substance is selected from the group consisting of analgesics,
anesthetics, radiosensitizers, lidocaine, and paclitaxel.
239. The article of claim 225, wherein the biologically active
substance is selected from the group consisting of analgesics,
anesthetics, radiosensitizers, lidocaine, and paclitaxel.
240. The article of claim 226, wherein the biologically active
substance is selected from the group consisting of analgesics,
anesthetics, radiosensitizers, lidocaine, and paclitaxel.
241. The article of claim 227, wherein the biologically active
substance is selected from the group consisting of analgesics,
anesthetics, radiosensitizers, lidocaine, and paclitaxel.
242. The article of claim 228, wherein the biologically active
substance is selected from the group consisting of analgesics,
anesthetics, radiosensitizers, lidocaine, and paclitaxel.
243. The article of claim 229, wherein the biologically active
substance is selected from the group consisting of analgesics,
anesthetics, radiosensitizers, lidocaine, and paclitaxel.
244. The article of claim 230, wherein the biologically active
substance is selected from the group consisting of analgesics,
anesthetics, radiosensitizers, lidocaine, and paclitaxel.
245. The article of claim 231, wherein the biologically active
substance is selected from the group consisting of analgesics,
anesthetics, radiosensitizers, lidocaine, and paclitaxel.
246. The article of claim 232, wherein the biologically active
substance is selected from the group consisting of analgesics,
anesthetics, radiosensitizers, lidocaine, and paclitaxel.
247. The article of claim 233, wherein the biologically active
substance is selected from the group consisting of analgesics,
anesthetics, radiosensitizers, lidocaine, and paclitaxel.
248. The biodegradable polymer of claim 1, comprising the recurring
monomeric units shown in formula I: wherein:
X is --O-- or --NR'--, where R' is H or alkyl;
L is a branched or straight chain aliphatic group having from 1-20
carbon atoms,
wherein the group L occurs once in the monomeric unit;
M.sub.1 is (1) a branched or straight chain aliphatic group having
from 1-20 carbon atoms; or (2) a branched or straight chain oxy-,
carboxy- or amino-aliphatic group having from 1-20 carbon
atoms,
Y is --O--, --S-- or --NR'--;
R is H, alkyl, alkoxy, aryl, aryloxy, heterocyclic or
heterocycloxy;
the molar ratio of x:y is about 1; and
the molar ratio of n:(x or y) is between about 200:1 and 1:200
wherein said biodegradable polymer is biocompatible before and upon
biodegredation.
249. The biodegradable polymer of claim 1, wherein at least one of
M.sub.1 and M.sub.2 has the formula --CHR.sup.2 --CO--O--CHR.sup.2
--, wherein R.sup.2 is selected from the group consisting of H and
alkyl.
250. The biodegradable polymer of claim 1, wherein at least one of
M.sub.1 and M.sub.2 contains a carboxy group and has from 1 to 7
carbon atoms.
251. The biodegradable polymer of claim 1, wherein at least one of
M.sub.1 and M.sub.2 has the formula --(CH.sub.2).sub.3
--CO--O--.
252. The biodegradable polymer of claim 1, wherein at least one of
M.sub.1 and M.sub.2 has the formula --CH.sub.2 CH.sub.2
--O--CH.sub.2 --CO--.
253. The biodegradable polymer of claim 1, wherein M.sub.1 and
M.sub.2 are each independently selected from the group consisting
of: methylene, ethylene, 1-methylethylene, 1,2-dimethylethylene,
n-propylene, trimethylene, isopropylene, 2,2-dimethylpropylene,
tert-butylene, n-pentylene, tert-pentylene, n-hexylene,
n-heptylene, n-octylene, n-nonylene, n-decylene, n-undecylene,
n-dodecylene, n-propylene, 2-vinylpropylene, n-butenylene,
3-ethenylbutylene, n-pentenylene, 4-(3-propenyl)hexylene,
n-octenylene, 1-(4-butyenyl)-3-methyldecylene,
2-(3-propenyl)dodecylene, hexadecenylene, ethynylene, propynylene,
3-(2-ethynyl)pentylene, n-hexynylene, 2-(2-propynyl)decylene,
2-chloro-n-decylene, 1-hydroxy-3-ethenylbutylene,
2-propyl-6-nitro-10-dodecynylene, ethoxylene, 2-methylethoxylene,
propoxylene, butoxylene, pentoxylene, dodecyloxylene,
hexadecyloxylene, dioxymethylene, dioxyethylene,
1,3-dioxypropylene, 2-methoxy-1,3-dioxypropylene,
1,3-dioxy-2-methylpropylene, dioxy-n-pentylene,
dioxy-n-octadecylene, methoxylene-methoxylene,
ethoxylene-methoxylene, ethoxylene-ethoxylene,
ethoxylene-1-propoxylene, butoxylene-n-propoxylene,
pentadecyloxylene-methoxylene, methyl formate, methyl acetate,
ethyl acetate, n-propyl acetate, isopropyl acetate, n-butyl
acetate, ethyl propionate, allyl propionate, t-butyl acrylate,
n-butyl butyrate, vinyl chloroacetate,
2-methoxy-carbonylcyclohexanone, and 2-acetoxycyclohexanone.
254. A biodegradable polymer prepared by the process comprising the
steps of reacting at least one heterocyclic ring compound having
formula III, IV or V: ##STR29## wherein X is --O-- or --NR'--,
where R' is H or alkyl;
M.sub.1 and M.sub.2 are each independently (1) a branched or
straight chain aliphatic group having from 1-20 carbon atoms; or
(2) a branched or straight chain, oxy-, carboxy- or amino-aliphatic
group having from 1-20 carbon atoms
with an initiator having the formula:
wherein Y is --O--, --S--, or --NR'-- and L is a branched or
straight chain aliphatic group having from 1-20 carbon atoms, to
form a prepolymer of formula VI or VII, shown below: ##STR30## and
further reacting said prepolymer of formula III, IV or V with a
phosphorodihalidate of formula VIII: ##STR31## where "halo" is Br,
Cl or I; and R is H, alkyl, alkoxy, aryl, aryloxy, heteroxyclic or
heterocycloxy.
255. The product of claim 254, wherein the prepolymer is of formula
VI.
256. The product of claim 255, wherein R is an alkoxy group.
257. The product of claim 255, wherein R is an alkyl group.
258. The product of claim 254, wherein Y is O.
259. The product of claim 254, wherein M.sub.1 and M.sub.2 are the
same.
260. The product of claim 254, wherein L is a branched or straight
chain aliphatic group of 1 to 7 carbon atoms.
Description
BACKGROUND OF THE INVENTION
1. Field of the Invention
The present invention relates to biodegradable polymer
compositions, in particular those containing both phosphate and
ester linkages in the polymer backbone and that degrade in vivo
into non-toxic residues. The polymers of the invention are
particularly useful as implantable medical devices and drug
delivery systems.
2. Description of the Prior Art
Biocompatible polymeric materials have been used extensively in
therapeutic drug delivery and medical implant device applications.
Sometimes, it is also desirable for such polymers to be, not only
biocompatible, but also biodegradable to obviate the need for
removing the polymer once its therapeutic value has been
exhausted.
Conventional methods of drug delivery, such as frequent periodic
dosing, are not ideal in many cases. For example, with highly toxic
drugs, frequent conventional dosing can result in high initial drug
levels at the time of dosing, often at near-toxic levels, followed
by low drug levels between doses that can be below the level of
their therapeutic value. However, with controlled drug delivery,
drug levels can be more nearly maintained at therapeutic, but
non-toxic, levels by controlled release in a predictable manner
over a longer term.
If a biodegradable medical device is intended for use as a drug
delivery or other controlled-release system, using a polymeric
carrier is one effective means to deliver the therapeutic agent
locally and in a controlled fashion, see Langer et al., "Chemical
and Physical Structures of Polymers as Carriers for Controlled
Release of Bioactive Agents", J. Macro Science, Rev. Macro. Chem.
Phys., C23(1), 61-126 (1983). As a result, less total drug is
required, and toxic side effects can be minimized. Polymers have
been used as carriers of therapeutic agents to effect a localized
and sustained release. See Leong et al., "Polymeric Controlled Drug
Delivery", Advanced Drug Delivery Reviews, 1:199-233 (1987); Langer
et al., "New Methods of Drug Delivery", Science, 249:1527-33
(1990); and Chien et al., Novel Drug Delivery Systems (1982). Such
delivery systems offer the potential of enhanced therapeutic
efficacy and reduced overall toxicity.
For a non-biodegradable matrix, the steps leading to release of the
therapeutic agent are water diffusion into the matrix, dissolution
of the therapeutic agent, and diffusion of the therapeutic agent
out through the channels of the matrix. As a consequence, the mean
residence time of the therapeutic agent existing in the soluble
state is longer for a non-biodegradable matrix than for a
biodegradable matrix, for which passage through the channels of the
matrix, while it may occur, is no longer required. Since many
pharmaceuticals have short half-lives, therapeutic agents can
decompose or become inactivated within the non-biodegradable matrix
before they are released. This issue is particularly significant
for many bio-macromolecules and smaller polypeptides, since these
molecules are generally hydrolytically unstable and have low
permeability through a polymer matrix. In fact, in a
non-biodegradable matrix, many bio-macromolecules aggregate and
precipitate, blocking the channels necessary for diffusion out of
the carrier matrix.
These problems are alleviated by using a biodegradable matrix that,
in addition to some diffusional release, also allows controlled
release of the therapeutic agent by degradation of the polymer
matrix. Examples of classes of synthetic polymers that have been
studied as possible biodegradable materials include polyesters
(Pitt et al., "Biodegradable Drug Delivery Systems Based on
Aliphatic Polyesters: Application to Contraceptives and Narcotic
Antagonists", Controlled Release of Bioactive Materials, 19-44
(Richard Baker et al. ed. 1980)); poly(amino acids) and
pseudo-poly(amino acids) (Pulapura et al., "Trends in the
Development of Bioresorbable Polymers for Medical Applications",
Journal of Biomaterials Applications, 6(1), 216-50 (1992));
polyurethanes (Bruin et al., "Biodegradable Lysine
Diisocyanate-based
Poly(glycolide-co-.epsilon.-caprolactone)-urethane Network in
Artificial Skin", Biomaterials, 11(4), 291-95 (1990));
polyorthoesters (Heller et al., "Release of Norethindrone from
Poly(OrthoEsters)", Polymer Engineering and Science, 21(11), 727-31
(1981)); and polyanhydrides (Leong et al., "Polyanhydrides for
Controlled Release of Bioactive Agents", Biomaterials 7(5), 364-71
(1986)). Specific examples of biodegradable materials that are used
as medical implant materials are polylactide, polyglycolide,
polydioxanone, poly(lactide-co-glycolide),
poly(glycolide-co-polydioxanone), polyanhydrides,
poly(glycolide-co-trimethylene carbonate), and
poly(glycolide-co-caprolactone).
Polymers having phosphate linkages, called poly(phosphates),
poly(phosphonates) and poly(phosphites), are known. See Penczek et
al., "Phosphorus-Containing Polymers", Handbook of Polymer
Synthesis, Part B, Chapter 17, 1077-1132 (Hans R. Kricheldorf ed.
1992). The respective structures of these three classes of
compounds, each having a different sidechain connected to the
phosphorus atom, are as follows: ##STR1##
The versatility of these polymers comes from the versatility of the
phosphorus atom, which is known for a multiplicity of reactions.
Its bonding can involve the 3p orbitals or various 3s-3p hybrids;
spd hybrids are also possible because of the accessible d orbitals.
Thus, the physico-chemical properties of the poly(phosphoesters)
can be readily changed by varying either the R or R' group. The
biodegradability of the polymer is due primarily to the
physiologically labile phosphoester bond in the backbone of the
polymer. By manipulating the backbone or the sidechain, a wide
range of biodegradation rates are attainable. Kadiyala et al.,
"Poly(phosphoesters): Synthesis, Physicochemical Characterization
and Biological Response", Biomedical Applications of Synthetic
Biodegradable Polymers, Chapter 3: 33-57 (Jeffrey O. Hollinger ed.,
1995).
An additional feature of poly(phosphoesters) is the availability of
functional side groups. Because phosphorus can be pentavalent, drug
molecules or other biologically active substances can be chemically
linked to the polymer. For example, drugs with --O-carboxy groups
may be coupled to the phosphorus via an ester bond, which is
hydrolyzable. The P--O--C group in the backbone also lowers the
glass transition temperature of the polymer and, importantly,
confers solubility in common organic solvents, which is desirable
for easy characterization and processing.
Friedman, U.S. Pat. No. 3,442,982, discloses a
poly(phosphoester-co-ester) polymer having, as its ester portion,
the following asymmetric group: ##STR2## The polymers of Friedman
are noted as being stable to hydrolysis, heat and light. (Column 1,
lines 42-44 and column 3, lines 74-75).
Starck et al., Canadian Patent No. 597,473, disclose
poly(phosphonates), and the incorporation of the phosphorus is said
to make the resulting polymers incombustible. (Column 6, lines
1-2). Engelhardt et al., U.S. Pat. No. 5,530,093 discloses a
multitude of textile finishing compositions having a wide variety
of polycondensate structures with phosphoester and ester recurring
units. The ester portions of Starck et al. and Engelhardt et al.
are oriented as follows:
There remains a need for materials such as the
poly(phosphoester-co-ester) compounds of the invention, which are
particularly well-suited for making biodegradable materials and
other biomedical applications.
SUMMARY OF THE INVENTION
The biodegradable polymers of the invention comprise the recurring
monomeric units shown in formula I or II: ##STR3## wherein: X is
--O-- or --NR'--, where R' is H or alkyl;
M.sub.1 and M.sub.2 are each independently (1) a branched or
straight chain aliphatic group having from 1-20 carbon atoms; or
(2) a branched or straight chain, oxy-, carboxy- or amino-aliphatic
group having from 1-20 carbon atoms;
Y is --O--, --S-- or --NR'--;
L is a branched or straight chain aliphatic group having from 1-20
carbon atoms;
R is H, alkyl, alkoxy, aryl, aryloxy, heterocyclic or
heterocycloxy;
the molar ratio of x:y is about 1;
the molar ratio of n:(x or y) is between about 200:1 and 1:200;
and
the molar ratio q:r is between about 1:99 and 99:1.
These biodegradable polymers are biocompatible before and upon
biodegradation.
In another embodiment, the invention comprises polymer compositions
comprising:
(a) at least one biologically active substance and
(b) a polymer having the recurring monomeric units shown in formula
I or II.
In yet another embodiment of the invention, an article useful for
implantation, injection, or otherwise being placed totally or
partially within the body, comprises the biodegradable polymer of
formula I or II or the above-described polymer compositions.
In a further embodiment, the invention contemplates a process for
preparing a biodegradable polymer comprising the steps of:
(a) reacting a heterocyclic ring compound having formula III, IV,
or V: ##STR4## wherein M.sub.1, M.sub.2 and X are as defined
above,
with an initiator having the formula:
wherein Y and L are as defined as above, to form a prepolymer of
formula VI or VII, shown below: ##STR5## wherein X, M.sub.1,
M.sub.2, Y, L, x, y, q and r are as defined above; and (b) further
reacting said prepolymer of formula III, IV or V with a
phosphorodihalidate of formula VIII: ##STR6## where "halo" is Br,
Cl or I; and R is as defined above, to form said polymer of formula
I or II.
In another embodiment of the invention, a method is provided for
the controlled release of a biologically active substance
comprising the steps of:
(a) combining the biologically active substance with a
biodegradable polymer having the recurring monomeric units shown in
formula I or II to form an admixture;
(b) forming the admixture into a shaped, solid article; and
(c) implanting or injecting the solid article in vivo at a
preselected site, such that the solid implanted or injected article
is in at least partial contact with a biological fluid.
BRIEF DESCRIPTION OF THE DRAWINGS
FIG. 1 shows the results of a GPC analysis of a polymer of the
invention in graphic form.
FIGS. 2A and 2B show differential scanning calorimetry data for two
polymers of the invention.
FIG. 3 shows the appearance of microspheres of a polymer of the
invention made by the solvent evaporation method.
FIGS. 4A and 4B show the weight loss (4A) and the change in Mw (4B)
for discs fabricated from two polymers of the invention over a
period of eight days in PBS at 37.degree. C.
FIG. 5 shows the change in Mw of two polymers of the invention
after being exposed to air at room temperature for one month.
FIG. 6 shows the .sup.1 H-NMR spectrum of a polymer of the
invention, P(LAEG-EOP).
FIG. 7 shows the .sup.31 P-NMR spectrum of a polymer of the
invention, P(LAEG-EOP).
FIG. 8 shows shelf stability data for a polymer of the invention at
room temperature.
FIG. 9 shows cytotoxicity data for microspheres of a polymer of the
invention, P(LAEG-EOP).
FIGS. 10A and 10B show the weight loss (10A) and the change in Mw
(10B) for discs fabricated from two polymers of the invention, in
vitro.
FIGS. 11A and 11B show the weight loss (11A) and the change in Mw
(11B) for discs fabricated from the polymer of the invention, in
vivo.
FIG. 12 shows biocompatibility data for polymers of the
invention.
FIG. 13 shows the effect of fabrication method upon the release
rate of microspheres of a polymer of the invention.
FIG. 14 shows the rate of release of lidocaine and cisplatin from
microspheres of a polymer of the invention.
FIG. 15 shows the appearance of microspheres of a polymer of the
invention containing FITC-BSA.
FIG. 16 shows the rate of release of lidocaine from microspheres of
a polymer of the invention.
FIG. 17 shows the rate of release of lidocaine from microspheres of
a polymer of the invention.
DETAILED DESCRIPTION OF THE INVENTION
Polymers of the Invention
As used herein, the term "aliphatic" refers to a linear, branched,
cyclic alkane, alkene, or alkyne. Preferred aliphatic groups in the
poly(phosphoester-co-ester) polymer of the invention are linear or
branched and have from 1 to 10 carbons, preferably being linear
groups having from 1 to 7 carbon atoms.
As used herein, the term "aryl" refers to an unsaturated cyclic
carbon compound with 4n+2 .pi. electrons.
As used herein, the term "heterocyclic" refers to a saturated or
unsaturated ring compound having one or more atoms other than
carbon in the ring, for example, nitrogen, oxygen or sulfur.
The biodegradable polymer of the invention comprises the recurring
monomeric units shown in formula I or II: ##STR7## wherein X is
--O-- or --NR'-- where R' is H or alkyl.
L can be any divalent branched or straight chain aliphatic group
having from 1-20 carbon atoms, so long as it does not interfere
with the polymerization or biodegradation reactions of the polymer.
Specifically, L can be an alkylene group, such as methylene,
ethylene, 1,2-dimethyl-ethylene, n-propylene, isopropylene,
2,2-dimethylpropylene or tert-butylene, n-pentylene,
tert-pentylene, n-hexylene, n-heptylene and the like; an alkylene
substituted with a non-interfering substituent, for example,
hydroxy-, halogen- or nitrogen-substituted alkylene; an alkenylene
group such as ethenylene, propenylene, 2-(3-propenyl)-dodecylene;
and an alkynylene group such as ethynylene, proynylene,
1-(4-butynyl)-3-methyldecylene; and the like.
Preferably, however, L is independently a branched or straight
chain alkylene group, more preferably, an alkylene group having
from 1 to 7 carbon atoms. Even more preferably, L is an ethylene
group or a methyl-substituted methylene group and, most preferably
L is an ethylene group.
M.sub.1 and M.sub.2 in the formula are each independently either
(1) a branched or straight chain aliphatic group having from 1-20
carbon atoms or (2) a branched or straight chain, oxy-, carboxy- or
amino-aliphatic group having from 1-20 carbon atoms. In either case
the branched or straight chain aliphatic group can be any divalent
aliphatic moiety having from 1-20 carbon atoms, preferably 1-7
carbon atoms, that does not interfere with the polymerization,
copolymerization or biodegradation reactions of the polymers.
Specifically, when either M.sub.1 or M.sub.2 is a branched or
straight chain aliphatic group having from 1-20 carbon atoms, it
can be, for example, an alkylene group, such as methylene,
ethylene, 1-methylethylene, 1,2-dimethylethylene, n-propylene,
trimethylene, isopropylene, 2,2-dimethylpropylene, tert-butylene,
n-pentylene, tert-pentylene, n-hexylene, n-heptylene, n-octylene,
n-nonylene, n-decylene, n-undecylene, n-dodecylene, and the like;
an alkenylene group, such as n-propenylene, 2-vinylpropylene,
n-butenylene, 3-ethenylbutylene, n-pentenylene,
4-(3-propenyl)hexylene, n-octenylene,
1-(4-butenyl)-3-methyldecylene, 2-(3-propenyl)dodecylene,
hexadecenylene and the like; an alkynylene group, such as
ethynylene, propynylene, 3-(2-ethynyl)pentylene, n-hexynylene,
2-(2-propynyl)decylene, and the like; or an alkylene, alkenylene or
alkynylene group substituted with a non-interfering substituent,
for example, a hydroxy, halogen or nitrogen group, such as
2-chloro-n-decylene, 1-hydroxy-3-ethenylbutylene,
2-propyl-6-nitro-10-dodecynylene, and the like.
When either M.sub.1 or M.sub.2 is a branched or straight chain,
oxy-aliphatic group having from 1-20 carbon atoms, it can be, for
example, a divalent alkoxylene group, such as ethoxylene,
2-methylethoxylene, propoxylene, butoxylene, pentoxylene,
dodecyloxylene, hexadecyloxylene, and the like. When M.sub.1 or
M.sub.2 is a branched or straight chain, oxy-aliphatic group,
preferably, it has the formula --O--(CH.sub.2).sub.a -- where a is
1 to 7.
When either M.sub.1 or M.sub.2 is a branched or straight chain,
oxy-aliphatic group having from 1-20 carbon atoms, it can also be,
for example, a dioxyalkylene group such as dioxymethylene,
dioxyethylene, 1,3-dioxypropylene, 2-methoxy-1,3-dioxypropylene,
1,3-dioxy-2-methylpropylene, dioxy-n-pentylene,
dioxy-n-octadecylene, methoxylene-methoxylene,
ethoxylene-methoxylene, ethoxylene-ethoxylene,
ethoxylene-1-propoxylene, butoxylene-n-propoxylene,
pentadecyloxylene-methoxylene, and the like. When M.sub.1 or
M.sub.2 is a branched or straight chain, dioxo-aliphatic group,
preferably it has the formula --O--(CH.sub.2).sub.a --O-- or
--O--(CH.sub.2).sub.a --O--(CH.sub.2).sub.b --, wherein each of a
and b is from 1 to 7.
When either M.sub.1 or M.sub.2 is a branched or straight chain,
carboxy-aliphatic group having from 1-20 carbon atoms, it can also
be, for example, a divalent carboxylic acid ester such as the
divalent radical of methyl formate, methyl acetate, ethyl acetate,
n-propyl acetate, isopropyl acetate, n-butyl acetate, ethyl
propionate, allyl propionate, t-butyl acrylate, n-butyl butyrate,
vinyl chloroacetate, 2-methoxy-carbonylcyclohexanone,
2-acetoxycyclohexanone, and the like. When M.sub.1 or M.sub.2 is a
branched or straight chain, carboxy-aliphatic group, it preferably
has the formula --O--CHR.sup.2 --CO--O--CHR.sup.3 --, wherein
R.sup.2 and R.sup.3 are each independently H, alkyl, alkoxy, aryl,
aryloxy, heterocyclic or heterocycloxy.
When either M.sub.1 or M.sub.2 is a branched or straight chain,
amino-aliphatic group having from 1-20 carbon atoms, it can be a
divalent amine such as --CH.sub.2 NH--, --(CH.sub.2).sub.2 N--,
--CH.sub.2 (C.sub.2 H.sub.5)N--, -n-C.sub.4 H.sub.9 NH--,
-t--C.sub.4 H.sub.9 NH--, --CH.sub.2 (C.sub.3 H.sub.7)N--,
--C.sub.2 H.sub.5 (C.sub.3 H.sub.7)N--, --CH.sub.2 (C.sub.8
H.sub.17)N--, and the like. When M.sub.1 or M.sub.2 is a branched
or straight chain, amino-aliphatic group, it preferably has the
formula --(CH.sub.2).sub.a --NR'-- where R' is H or lower
alkyl.
Preferably, M.sub.1 and/or M.sub.2 is an alkylene group having the
formula --O--(CH2).sub.a -- where a is 1 to 7 and, most preferably,
is a divalent ethylene group. In a particularly preferred
embodiment, M.sub.1 and M.sub.2 are both present; M.sub.1 and
M.sub.2 are not the same chemical entity; and M.sub.1 and M.sub.2
are n-pentylene and the divalent radical of methyl acetate
respectively.
R in the polymer of the invention is H, alkyl, alkoxy, aryl,
aryloxy, heterocyclic or heterocycloxy residue. Examples of useful
alkyl R' groups include methyl, ethyl, n-propyl, i-propyl, n-butyl,
tert-butyl, --C.sub.8 H.sub.17, and the like groups; alkyl
substituted with a non-interfering substituent, such as hydroxy,
halogen, alkoxy or nitro; corresponding alkoxy groups; and alkyl
conjugated to a biologically active substance to form a pendant
drug delivery system.
When R is aryl or the corresponding aryloxy group, it typically
contains from about 5 to about 14 carbon atoms, preferably about 5
to 12 carbon atoms and, optionally, can contain one or more rings
that are fused to each other. Examples of particularly suitable
aromatic groups include phenyl, phenoxy, naphthyl, anthracenyl,
phenanthrenyl and the like.
When R is heterocyclic or heterocycloxy, it typically contains from
about 5 to 14 ring atoms, preferably from about 5 to 12 ring atoms,
and one or more heteroatoms. Examples of suitable heterocyclic
groups include furan, thiophene, pyrrole, isopyrrole, 3-isopyrrole,
pyrazole, 2-isoimidazole, 1,2,3-triazole, 1,2,4-triazole, oxazole,
thiazole, isothiazole, 1,2,3-oxadiazole, 1,2,4-oxadiazole,
1,2,5-oxadiazole, 1,3,4-oxadiazole, 1,2,3,4-oxatriazole,
1,2,3,5-oxatriazole, 1,2,3-dioxazole, 1,2,4-dioxazole,
1,3,2-dioxazole, 1,3,4-dioxazole, 1,2,5-oxatriazole, 1,3-oxathiole,
1,2-pyran, 1,4-pyran, 1,2-pyrone, 1,4-pyrone, 1,2-dioxin,
1,3-dioxin, pyridine, N-alkyl pyridinium, pyridazine, pyrimidine,
pyrazine, 1,3,5-triazine, 1,2,4-triazine, 1,2,3-triazine,
1,2,4-oxazine, 1,3,2-oxazine, 1,3,5-oxazine, 1,4-oxazine,
o-isoxazine, p-isoxazine, 1,2,5-oxathiazine, 1,2,6-oxathiazine,
1,4,2-oxadiazine, 1,3,5,2-oxadiazine, azepine, oxepin, thiepin,
1,2,4-diazepine, indene, isoindene, benzofuran, isobenzofuran,
thionaphthene, isothionaphthene, indole, indolenine,
2-isobenzazole, 1,4-pyrindine, pyrando(3,4-b)-pyrrole, isoindazole,
indoxazine, benzoxazole, anthranil, 1,2-benzopyran,
1,2-benzopyrone, 1,4-benzopyrone, 2,1-benzopyrone, 2,3-benzopyrone,
quinoline, isoquinoline, 12, -benzodiazine, 1,3-benzodiazine,
naphthyridine, pyrido(3,4-b)-pyridine, pyrido(3,2-b)-pyridine,
pyrido(4,3-b)pyridine, 1,3,2-benzoxazine, 1,4,2-benzoxazine,
2,3,1-benzoxazine, 3,1,4-benzoxazine, 1,2-benzisoxazine,
1,4-benzisoxazine, carbazole, xanthrene, acridine, purine, and the
like. Preferably, when R is heterocyclic or heterocycloxy, it is
selected from the group consisting of furan, pyridine,
N-alkylpyridine, 1,2,3- and 1,2,4-triazoles, indene, anthracene and
purine rings.
In a particularly preferred embodiment, R is an alkyl group, an
alkoxy group, a phenyl group, a phenoxy group, or a heterocycloxy
group and, even more preferably, an alkoxy group having from 1 to 7
carbon atoms. Most preferably, R is an ethoxy group.
The molar ratio of n:(x or y) can vary greatly depending on the
biodegradability and the release characteristics desired in the
polymer, but typically varies between about 200:1 and 1:200.
Preferably, the ratio n:(x or y) is from about 100:1 to about 1:100
and, most preferably, from about 50:1 to about 1:50. Each of x and
y range from about 1 to 1,000 or more.
The molar ratio of q:r can vary greatly depending on the
biodegradability and the release characteristics desired in the
polymer, but typically varies between about 1:200 and 200:1.
Preferably, the ratio q:r is from about 1:150 to about 150:1 and,
most preferably, from about 1:99 to about 99:1.
The molar ratio of x:y can also vary greatly depending on the
biodegradability and the release characteristics desired in the
polymer but, typically, is about 1.
Biodegradable polymers differ from non-biodegradable polymers in
that they can be degraded during in vivo therapy. This generally
involves breaking down the polymer into its monomeric subunits. In
principle, the ultimate hydrolytic breakdown products of a
poly(phosphoester) are phosphate, alcohol, and diol, all of which
are potentially non-toxic. The intermediate oligomeric products of
the hydrolysis may have different properties, but the toxicology of
a biodegradable polymer intended for implantation or injection,
even one synthesized from apparently innocuous monomeric
structures, is typically determined after one or more in vitro
toxicity analyses. A typical toxicity assay would be performed with
live carcinoma cells, such as GT3TKB tumor cells, in the following
manner:
About 100-150 mg of the sample polymer is degraded in 20 mL of 1M
NaOH at 37.degree. C. for 1-2 days, or until complete degradation
is observed. The solution is then neutralized with 20 mL of 1M HCl.
About 200 .mu.L of various concentrations of the degraded polymer
products are placed in 96-well tissue culture plates and seeded
with human gastric carcinoma cells (GT3TKB) at 10.sup.4 /well
density. The degraded polymer products are incubated with the
GT3TKB cells for 48 hours. The results of the assay can be plotted
as % relative growth vs. concentration of degraded polymer in the
tissue-culture well.
The biodegradable polymer of the invention is preferably
sufficiently pure to be biocompatible itself and remains
biocompatible upon biodegradation. By "biocompatible" is meant that
the biodegradation products or the polymer itself are non-toxic and
result in only minimal tissue irritation when implanted or injected
into vasculated tissue.
The polymer of the invention is preferably soluble in one or more
common organic solvents for ease of fabrication and processing.
Common organic solvents include such solvents as chloroform,
dichloromethane, acetone, ethyl acetate, DMAC, N-methyl
pyrrolidone, dimethylformamide, and dimethylsulfoxide. The polymer
is preferably soluble in at least one of the above solvents.
Synthesis of Poly(phosphoester-co-ester) Polymers
The most common general reaction in preparing poly(phosphates) is a
dehydrochlorination between a phosphorodichloridate and a diol
according to the following equation: ##STR8## Most
poly(phosphonates) are also obtained by condensation between
appropriately substituted dichlorides and diols.
Poly(phosphites) have been prepared from glycols in a two-step
condensation reaction. A 20% molar excess of a dimethylphosphite is
used to react with the glycol, followed by the removal of the
methoxyphosphonyl end groups in the oligomers by high
temperature.
An advantage of melt polycondensation is that it avoids the use of
solvents and large amounts of other additives, thus making
purification more straightforward. It can also provide polymers of
reasonably high molecular weight. Somewhat rigorous conditions,
however, are often required and can lead to chain acidolysis (or
hydrolysis if water is present). Unwanted, thermally-induced side
reactions, such as cross-linking reactions, can also occur if the
polymer backbone is susceptible to hydrogen atom abstraction or
oxidation with subsequent macroradical recombination.
To minimize these side reactions, the polymerization can also be
carried out in solution. Solution polycondensation requires that
both the prepolymer and the phosphorus component be soluble in a
common solvent. Typically, a chlorinated organic solvent is used,
such as chloroform, dichloromethane, or dichloroethane. The
solution polymerization must be run in the presence of equimolar
amounts of the reactants and a stoichiometric amount of an acid
acceptor, usually a tertiary amine such as pyridine or
triethylamine. The product is then typically isolated from the
solution by precipitation in a non-solvent and purified to remove
the hydrochloride salt by conventional techniques known to those of
ordinary skill in the art, such as by washing with an aqueous
acidic solution, e.g., dilute HCl.
Reaction times tend to be longer with solution polymerization than
with melt polymerization. However, because overall milder reaction
conditions can be used, side reactions are minimized, and more
sensitive functional groups can be incorporated into the polymer.
The disadvantages of solution polymerization are that the
attainment of high molecular weights, such as a Mw greater than
20,000, is less likely.
Interfacial polycondensation can be used when high molecular weight
polymers are desired at high reaction rates. Mild conditions
minimize side reactions. Also the dependence of high molecular
weight on stoichiometric equivalence between diol and dichloridate
inherent in solution methods is removed. However, hydrolysis of the
acid chloride may occur in the alkaline aqueous phase. Sensitive
dichloridates that have some solubility in water are generally
subject to hydrolysis rather than polymerization. Phase transfer
catalysts, such as crown ethers or tertiary ammonium chloride, can
be used to bring the ionized diol to the interface to facilitate
the polycondensation reaction. The yield and molecular weight of
the resulting polymer after interfacial polycondensation are
affected by reaction time, molar ratio of the monomers, volume
ratio of the immiscible solvents, the type of acid acceptor, and
the type and concentration of the phase transfer catalyst.
In a preferred embodiment of the invention, the biodegradable
polymer of formula I or II is made by a process comprising the
steps of:
(a) reacting at least one heterocyclic ring compound having formula
III, IV or V: ##STR9## wherein M.sub.1, M.sub.2 and X are as
defined above, with an initiator having the formula:
wherein Y and L are as defined as above, to form a prepolymer of
formula VI or VII, shown below: ##STR10## wherein X, M.sub.1,
M.sub.2, Y, L, R, x, y, q and r are as defined above; and
(b) further reacting said prepolymer of formula III, or IV or V
with a phosphorodihalidate of formula VIII: ##STR11## where "halo"
is Br, Cl or I; and R is as defined above, to form said polymer of
formula I or II.
The function of the first reaction step (a) is to use the initiator
to open the ring of the heterocyclic ring compound of formula III,
IV or V. Examples of useful heterocyclic compounds of formula III,
IV or V include caprolactones, caprolactams, amino acid anhydrides
such as glycine anhydride, cycloalkylene carbonates, dioxanones,
glycolids, lactides and the like.
When the compound of the invention has formula I, only one
heterocyclic ring compound of formula III, which contains M.sub.1,
may be used to prepare the prepolymer of formula VI in step (a).
When the compound of the invention has formula II, then a
combination of a heterocyclic compound of formula III, which
contains M.sub.1, and a heterocyclic compound of formula IV, which
contains M.sub.2, may be used in step (a). Alternatively, when the
compound of the invention has formula II, a single heterocyclic
compound of formula V, which contains both M.sub.1 and M.sub.2, can
be used in step (a).
Examples of suitable initiators include a wide variety of compounds
having at least two active hydrogens (H--Y--L--Y--H) where L is a
linking group and is defined above, and Y can be --O--, --S-- or
--NR", where R" is as defined above. The linking group L is can be
a straight chain group, e.g., alkylene, but it may also be
substituted with one or more additional active-hydrogen-containing
groups. For example, L may a straight chain alkylene group
substituted with one or more additional alkyl groups, each bearing
a activated hydrogen moiety, such as --OH, --SH, or NH.sub.2. In
this way, various branched polymers can be prepared using the
branched active hydrogen initiators to design the resulting polymer
such that it has the desired properties. However, when branched
polymers are reacted with acid chlorides, cross-linked polymers
will result.
The reaction step (a) can take place at widely varying
temperatures, depending upon the solvent used, the molecular weight
desired, the susceptibility of the reactants to form side
reactions, and the presence of a catalyst. Preferably, however, the
reaction step (a) takes place at a temperature from about 0 to
about +235.degree. C. for melt conditions. Somewhat lower
temperatures may be possible with the use of either a cationic or
anionic catalyst.
The time required for the reaction step (a) also can vary widely,
depending on the type of reaction being used and the molecular
weight desired. Preferably, however, the reaction step (a) takes
place during a time between about 1 hour and 7 days.
While the reaction step (a) may be in bulk, in solution, by
interfacial polycondensation, or any other convenient method of
polymerization, preferably, the reaction step (a) takes place under
melt conditions.
Examples of particularly useful prepolymers of formula V
include:
(i) OH-terminated prepolymer derived from polycaprolactone
H--(--O(CH.sub.2).sub.5 --CO--).sub.x --O--CH.sub.2 --CH.sub.2
--O--(--CO--(CH.sub.2).sub.5 --O--).sub.y --H;
(ii) NH-terminated prepolymer derived from polycaprolactam (Nylon
6) H--(--NH--(CH.sub.2).sub.5 --CO--).sub.x --NH--CH.sub.2
--CH.sub.2 --NH--(--CO--(CH.sub.2).sub.5 --NH--).sub.y --H;
(iii) OH-terminated prepolymer derived from polylactide
H--(--OCH(CH.sub.3)--CO--).sub.x--O--CH.sub.2 --CH.sub.2
--O--(--CO--CH(CH.sub.3)--O--).sub.y --H; and
(iv) OH-terminated prepolymer derived from polytrimethylene
carbonate H--(--O(CH.sub.2).sub.3 --O--CO--).sub.x --O--CH.sub.2
--CH.sub.2 --O--(--CO--O--(CH.sub.2).sub.3 --O--).sub.y --H.
Examples of particularly useful prepolymers of formula VI
include:
(i) OH-terminated copolymer derived from lactide and glycolide:
##STR12## (ii) OH-terminated copolymer derived from lactide and
caprolactone: ##STR13## and (iii) OH-terminated copolymer derived
from glycolide and caprolactone: ##STR14##
The purpose of the polymerization of step (b) is to form a polymer
comprising (i) the prepolymer produced as a result of step (a) and
(ii) interconnecting phosphorylated units. The result can be a
block copolymer having a microcrystalline structure that is
particularly well-suited to use as a controlled release medium.
The polymerization step (b) of the invention usually takes place at
a slightly lower temperature than the temperature of step (a), but
also may vary widely, depending upon the type of polymerization
reaction used, the presence of one or more catalysts, the molecular
weight desired, and the susceptibility of the reactants to
undesirable side reaction. When melt conditions are used, the
temperature may vary from about 0-150.degree. C. However, when the
polymerization step (b) is carried out in a solution polymerization
reaction, it typically takes place at a temperature between about
-40 and 100.degree. C. Typical solvents include methylene chloride,
chloroform, or any of a wide variety of inert organic solvents.
The time required for the polymerization of step (b) can also vary
widely, depending on the molecular weight of the material desired
and, in general, the need to use more or less rigorous conditions
for the reaction to proceed to the desired degree of completion.
Typically, however, the polymerization step (b) takes place during
a time of about 30 minutes to 48 hours.
Particularly when solution polymerization reaction is used, an acid
acceptor is advantageously present during the polymerization step
(a). A particularly suitable class of acid acceptor comprises
tertiary amines, such as pyridine, trimethylamine, triethylamine,
substituted anilines and substituted aminopyridines. The most
preferred acid acceptor is the substituted aminopyridine
4-dimethyl-aminopyridine ("DMAP").
The polymers of formula I and II are isolated from the reaction
mixture by conventional techniques, such as by precipitating out,
extraction with an immiscible solvent, evaporation, filtration,
crystallization and the like. Typically, however, the polymers of
formulas I and II are both isolated and purified by quenching a
solution of said polymer with a non-solvent or a partial solvent,
such as diethyl ether or petroleum ether.
Biodegradability and Release Characteristics
The polymers of formulas I and II are usually characterized by a
release rate of the biologically active substance in vivo that is
controlled at least in part as a function of hydrolysis of the
phosphoester bond of the polymer during biodegradation.
Additionally, the biologically active substance to be released may
be conjugated to the phosphorus sidechain R' to form a pendant drug
delivery system. Further, other factors are also important.
The life of a biodegradable polymer in vivo also depends upon its
molecular weight, crystallinity, biostability, and the degree of
cross-linking. In general, the greater the molecular weight, the
higher the degree of crystallinity, and the greater the
biostability, the slower biodegradation will be.
Accordingly, the structure of the sidechain can influence the
release behavior of compositions comprising a biologically active
substance. For example, it is expected that conversion of the
phosphate sidechain to a more lipophilic, more hydrophobic or bulky
group would slow down the degradation process. Thus, release is
usually faster from polymer compositions with a small aliphatic
group sidechain than with a bulky aromatic sidechain.
Polymer Compositions
The polymers of formulas I and II can be used either alone or as a
composition containing, in addition, a biologically active
substance to form a variety of useful biodegradable materials. For
example, the polymers of formulas I and II can be used to produce a
biosorbable suture, an orthopedic appliance or bone cement for
repairing injuries to bone or connective tissue, a laminate for
degradable or non-degradable fabrics, or a coating for an
implantable device, even without the presence of a biologically
active substance.
Preferably, however, the biodegradable polymer composition
comprises both:
(a) at least one biologically active substance and
(b) the polymer having the recurring monomeric units shown in
formula I or II where X, M.sub.1, M.sub.2, L, R, Y, x, y, q, r and
n are as defined above.
The biologically active substance of the invention can vary widely
with the purpose for the composition. The active substance(s) may
be described as a single entity or a combination of entities. The
delivery system is designed to be used with biologically active
substances having high water-solubility as well as with those
having low water-solubility to produce a delivery system that has
controlled release rates. The term "biologically active substance"
includes without limitation, medicaments; vitamins; mineral
supplements; substances used for the treatment, prevention,
diagnosis, cure or mitigation of disease or illness; or substances
which affect the structure or function of the body; or pro-drugs,
which become biologically active or more active after they have
been placed in a predetermined physiological environment.
Non-limiting examples of broad categories of useful biologically
active substances include the following expanded therapeutic
categories: anabolic agents, antacids, anti-asthmatic agents,
anti-cholesterolemic and anti-lipid agents, anti-coagulants,
anti-convulsants, anti-diarrheals, anti-emetics, anti-infective
agents, anti-inflammatory agents, anti-manic agents,
anti-nauseants, anti-neoplastic agents, anti-obesity agents,
anti-pyretic and analgesic agents, anti-spasmodic agents,
anti-thrombotic agents, anti-uricemic agents, anti-anginal agents,
antihistamines, anti-tussives, appetite suppressants, biologicals,
cerebral dilators, coronary dilators, decongestants, diuretics,
diagnostic agents, erythropoietic agents, expectorants,
gastrointestinal sedatives, hyperglycemic agents, hypnotics,
hypoglycemic agents, ion exchange resins, laxatives, mineral
supplements, mucolytic agents, neuromuscular drugs, peripheral
vasodilators, psychotropics, sedatives, stimulants, thyroid and
anti-thyroid agents, uterine relaxants, vitamins, and prodrugs.
Specific examples of useful biologically active substances from the
above categories include: (a) anti-neoplastics such as androgen
inhibitors, antimetabolites, cytotoxic agents, immunomodulators;
(b) anti-tussives such as dextromethorphan, dextromethorphan
hydrobromide, noscapine, carbetapentane citrate, and chlorphedianol
hydrochloride; (c) antihistamines such as chlorpheniramine maleate,
phenindamine tartrate, pyrilamine maleate, doxylamine succinate,
and phenyltoloxamine citrate; (d) decongestants such as
phenylephrine hydrochloride, phenylpropanolamine hydrochloride,
pseudoephedrine hydrochloride, and ephedrine; (e) various alkaloids
such as codeine phosphate, codeine sulfate and morphine; (f)
mineral supplements such as potassium chloride, zinc chloride,
calcium carbonates, magnesium oxide, and other alkali metal and
alkaline earth metal salts; (g) ion exchange resins such as
cholestyramine; (h) anti-arrhythmics such as N-acetylprocainamide;
(i) antipyretics and analgesics such as acetaminophen, aspirin and
ibuprofen; (j) appetite suppressants such as phenyl-propanolamine
hydrochloride or caffeine; (k) expectorants such as guaifenesin;
(l) antacids such as aluminum hydroxide and magnesium hydroxide;
(m) biologicals such as peptides, polypeptides, proteins and amino
acids, hormones, interferons or cytokines and other bioactive
peptidic compounds, such as hGH, tPA, calcitonin, ANF, EPO and
insulin; and (n) anti-infective agents such as anti-fungals,
anti-virals, antiseptics and antibiotics.
Preferably, the biologically active substance is selected from the
group consisting of polysaccharides, growth factors, hormones,
anti-angiogenesis factors, interferons or cytokines, and pro-drugs.
More specifically, non-limiting examples of useful biologically
active substances include the following therapeutic categories:
analgesics, such as nonsteroidal anti-inflammatory drugs, opiate
agonists and salicylates; antihistamines, such as H.sub.1 -blockers
and H.sub.2 -blockers; anti-infective agents, such as
antihelmintics, antianaerobics, antibiotics, aminoglycoside
antibiotics, antifungal antibiotics, cephalosporin antibiotics,
macrolide antibiotics, miscellaneous .beta.-lactam antibiotics,
penicillin antibiotics, quinolone antibiotics, sulfonamide
antibiotics, tetracycline antibiotics, antimycobacterials,
antituberculosis antimycobacterials, antiprotozoals, antimalarial
antiprotozoals, antiviral agents, anti-retroviral agents,
scabicides, and urinary anti-infectives; antineoplastic agents,
such as alkylating agents, nitrogen mustard alkylating agents,
nitrosourea alkylating agents, antimetabolites, purine analog
antimetabolites, pyrimidine analog antimetabolites, hormonal
antineoplastics, natural antineoplastics, antibiotic natural
antineoplastics, and vinca alkaloid natural antineoplastics;
autonomic agents, such as anticholinergics, antimuscarinic
anticholinergics, ergot alkaloids, parasympathomimetics,
cholinergic agonist parasympathomimetics, cholinesterase inhibitor
parasympathomimetics, sympatholytics, .alpha.-blocker
sympatholytics, .beta.-blocker sympatholytics, sympathomimetics,
and adrenergic agonist sympathomimetics; cardiovascular agents,
such as antianginals, .beta.-blocker antianginals, calcium-channel
blocker antianginals, nitrate antianginals, antiarrhythmics,
cardiac glycoside antiarrhythmics, class I antiarrhythmics, class
II antiarrhythmics, class III antiarrhythmics, class IV
antiarrhythmics, antihypertensive agents, .alpha.-blocker
antihypertensives, angiotensin-converting enzyme inhibitor (ACE
inhibitor) antihypertensives, .beta.-blocker antihypertensives,
calcium-channel blocker antihypertensives, central-acting
adrenergic anti-hypertensives, diuretic antihypertensive agents,
peripheral vasodilator antihypertensives, antilipemics, bile acid
sequestrant antilipemics, HMG-CoA reductase inhibitor antilipemics,
inotropes, cardiac glycoside inotropes, and thrombolytic agents;
dermatological agents, such as antihistamines, anti-inflammatory
agents, corticosteroid anti-inflammatory agents,
antipruritics/local anesthetics, topical anti-infectives,
antifungal topical anti-infectives, antiviral topical
anti-infectives, and topical anti-neoplastics; electrolytic and
renal agents, such as acidifying agents, alkalinizing agents,
diuretics, carbonic anhydrase inhibitor diuretics, loop diuretics,
osmotic diuretics, potassium-sparing diuretics, thiazide diuretics,
electrolyte replacements, and uricosuric agents; enzymes, such as
pancreatic enzymes and thrombolytic enzymes; gastrointestinal
agents, such as antidiarrheals, anti-emetics, gastrointestinal
anti-inflammatory agents, salicylate gastrointestinal
anti-inflammatory agents, antacid anti-ulcer agents, gastric
acid-pump inhibitor anti-ulcer agents, gastric mucosal anti-ulcer
agents, H.sub.2 -blocker anti-ulcer agents, cholelitholytic agents,
digestants, emetics, laxatives and stool softeners, and prokinetic
agents; general anesthetics, such as inhalation anesthetics,
halogenated inhalation anesthetics, intravenous anesthetics,
barbiturate intravenous anesthetics, benzodiazepine intravenous
anesthetics, and opiate agonist intravenous anesthetics;
hematological agents, such as antianemia agents, hematopoietic
antianemia agents, coagulation agents, anticoagulants, hemostatic
coagulation agents, platelet inhibitor coagulation agents,
thrombolytic enzyme coagulation agents, and plasma volume
expanders; hormones and hormone modifiers, such as abortifacients,
adrenal agents, corticosteroid adrenal agents, androgens,
anti-androgens, antidiabetic agents, sulfonylurea antidiabetic
agents, antihypoglycemic agents, oral contraceptives, progestin
contraceptives, estrogens, fertility agents, oxytocics, parathyroid
agents, pituitary hormones, progestins, antithyroid agents, thyroid
hormones, and tocolytics; immunobiologic agents, such as
immunoglobulins, immunosuppressives, toxoids, and vaccines; local
anesthetics, such as amide local anesthetics and ester local
anesthetics; musculoskeletal agents, such as anti-gout
anti-inflammatory agents, corticosteroid anti-inflammatory agents,
gold compound anti-inflammatory agents, immunosuppressive
anti-inflammatory agents, nonsteroidal anti-inflammatory drugs
(NSAIDs), salicylate anti-inflammatory agents, skeletal muscle
relaxants, neuro-muscular blocker skeletal muscle relaxants, and
reverse neuromuscular blocker skeletal muscle relaxants;
neurological agents, such as anticonvulsants, barbiturate
anticonvulsants, benzodiazepine anticonvulsants, anti-migraine
agents, anti-parkinsonian agents, anti-vertigo agents, opiate
agonists, and opiate antagonists; ophthalmic agents, such as
anti-glaucoma agents, .beta.-blocker anti-glaucoma agents, miotic
anti-glaucoma agents, mydriatics, adrenergic agonist mydriatics,
antimuscarinic mydriatics, ophthalmic anesthetics, ophthalmic
anti-infectives, ophthalmic aminoglycoside anti-infectives,
ophthalmic macrolide anti-infectives, ophthalmic quinolone
anti-infectives, ophthalmic sulfonamide anti-infectives, ophthalmic
tetracycline anti-infectives, ophthalmic anti-inflammatory agents,
ophthalmic corticosteroid anti-inflammatory agents, and ophthalmic
nonsteroidal anti-inflammatory drugs (NSAIDs); psychotropic agents,
such as antidepressants, heterocyclic antidepressants, monoamine
oxidase inhibitors (MAOIs), selective serotonin re-uptake
inhibitors (SSRIs), tricyclic antidepressants, antimanics,
antipsychotics, phenothiazine antipsychotics, anxiolytics,
sedatives, and hypnotics, barbiturate sedatives and hypnotics,
benzodiazepine anxiolytics, sedatives, and hypnotics, and
psychostimulants; respiratory agents, such as antitussives,
bronchodilators, adrenergic agonist bronchodilators, antimuscarinic
bronchodilators, expectorants, mucolytic agents, respiratory
anti-inflammatory agents, and respiratory corticosteroid
anti-inflammatory agents; toxicology agents, such as antidotes,
heavy metal antagonists/chelating agents, substance abuse agents,
deterrent substance abuse agents, and withdrawal substance abuse
agents; minerals; and vitamins, such as vitamin A, vitamin B,
vitamin C, vitamin D, vitamin E, and vitamin K.
Preferred classes of useful biologically active substances from the
above categories include: (1) nonsteroidal anti-inflammatory drugs
(NSAIDs) analgesics, such as diclofenac, ibuprofen, ketoprofen, and
naproxen; (2) opiate agonist analgesics, such as codeine, fentanyl,
hydromorphone, and morphine; (3) salicylate analgesics, such as
aspirin (ASA) (enteric coated ASA); (4) H.sub.1 -blocker
antihistamines, such as clemastine and terfenadine; (5) H.sub.2
-blocker antihistamines, such as cimetidine, famotidine, nizadine,
and ranitidine; (6) anti-infective agents, such as mupirocin; (7)
antianaerobic anti-infectives, such as chloramphenicol and
clindamycin; (8) antifungal antibiotic anti-infectives, such as
amphotericin b, clotrimazole, fluconazole, and ketoconazole; (9)
macrolide antibiotic anti-infectives, such as azithromycin and
erythromycin; (10) miscellaneous .beta.-lactam antibiotic
anti-infectives, such as aztreonam and imipenem; (11) penicillin
antibiotic anti-infectives, such as nafcillin, oxacillin,
penicillin G, and penicillin V; (12) quinolone antibiotic
anti-infectives, such as ciprofloxacin and norfloxacin; (13)
tetracycline antibiotic anti-infectives, such as doxycycline,
minocycline, and tetracycline; (14) antituberculosis
antimycobacterial anti-infectives such as isoniazid (INH), and
rifampin; (15) antiprotozoal anti-infectives, such as atovaquone
and dapsone; (16) antimalarial antiprotozoal anti-infectives, such
as chloroquine and pyrimethamine; (17) anti-retroviral
anti-infectives, such as ritonavir and zidovudine; (18) antiviral
anti-infective agents, such as acyclovir, ganciclovir, interferon
alfa, and rimantadine; (19) alkylating antineoplastic agents, such
as carboplatin and cisplatin; (20) nitrosourea alkylating
antineoplastic agents, such as carmustine (BCNU); (21)
antimetabolite antineoplastic agents, such as methotrexate; (22)
pyrimidine analog antimetabolite antineoplastic agents, such as
fluorouracil (5-FU) and gemcitabine; (23) hormonal antineoplastics,
such as goserelin, leuprolide, and tamoxifen; (24) natural
antineoplastics, such as aldesleukin, interleukin-2, docetaxel,
etoposide (VP-16), interferon alfa, paclitaxel, and tretinoin
(ATRA); (25) antibiotic natural antineoplastics, such as bleomycin,
dactinomycin, daunorubicin, doxorubicin, and mitomycin; (26) vinca
alkaloid natural antineoplastics, such as vinblastine and
vincristine; (27) autonomic agents, such as nicotine; (28)
anticholinergic autonomic agents, such as benztropine and
trihexyphenidyl; (29) antimuscarinic anticholinergic autonomic
agents, such as atropine and oxybutynin; (30) ergot alkaloid
autonomic agents, such as bromocriptine; (31) cholinergic agonist
parasympathomimetics, such as pilocarpine; (32) cholinesterase
inhibitor parasympathomimetics, such as pyridostigmine; (33)
.alpha.-blocker sympatholytics, such as prazosin; (34)
.beta.-blocker sympatholytics, such as atenolol; (35) adrenergic
agonist sympathomimetics, such as albuterol and dobutamine; (36)
cardiovascular agents, such as aspirin (ASA) (enteric coated ASA);
(37) .beta.-blocker antianginals, such as atenolol and propranolol;
(38) calcium-channel blocker antianginals, such as nifedipine and
verapamil; (39) nitrate antianginals, such as isosorbide dinitrate
(ISDN); (40) cardiac glycoside antiarrhythmics, such as digoxin;
(41) class I antiarrhythmics, such as lidocaine, mexiletine,
phenytoin, procainamide, and quinidine; (42) class II
antiarrhythmics, such as atenolol, metoprolol, propranolol, and
timolol; (43) class III antiarrhythmics, such as amiodarone; (44)
class IV antiarrhythmics, such as diltiazem and verapamil; (45)
.alpha.-blocker antihypertensives, such as prazosin; (46)
angiotensin-converting enzyme inhibitor (ACE inhibitor)
antihypertensives, such as captopril and enalapril; (47)
.beta.-blocker antihypertensives, such as atenolol, metoprolol,
nadolol, and propranolol; (48) calcium-channel blocker
antihypertensive agents, such as diltiazem and nifedipine; (49)
central-acting adrenergic antihypertensives, such as clonidine and
methyldopa; (50) diuretic antihypertensive agents, such as
amiloride, furosemide, hydrochlorothiazide (HCTZ), and
spironolactone; (51) peripheral vasodilator antihypertensives, such
as hydralazine and minoxidil; (52) antilipemics, such as
gemfibrozil and probucol; (53) bile acid sequestrant antilipemics,
such as cholestyramine; (54) HMG-CoA reductase inhibitor
antilipemics, such as lovastatin and pravastatin; (55) inotropes,
such as amrinone, dobutamine, and dopamine; (56) cardiac glycoside
inotropes, such as digoxin; (57) thrombolytic agents, such as
alteplase (TPA), anistreplase, streptokinase, and urokinase; (58)
dermatological agents, such as colchicine, isotretinoin,
methotrexate, minoxidil, tretinoin (ATRA); (59) dermatological
corticosteroid anti-inflammatory agents, such as betamethasone and
dexamethasone; (60) antifungal topical anti-infectives, such as
amphotericin B, clotrimazole, miconazole, and nystatin; (61)
antiviral topical anti-infectives, such as acyclovir; (62) topical
antineoplastics, such as fluorouracil (5-FU); (63) electrolytic and
renal agents, such as lactulose; (64) loop diuretics, such as
furosemide; (65) potassium-sparing diuretics, such as triamterene;
(66) thiazide diuretics, such as hydrochlorothiazide (HCTZ); (67)
uricosuric agents, such as probenecid; (68) enzymes such as RNase
and DNase; (69) thrombolytic enzymes, such as alteplase,
anistreplase, streptokinase and urokinase; (70) antiemetics, such
as prochlorperazine; (71) salicylate gastrointestinal
anti-inflammatory agents, such as sulfasalazine; (72) gastric
acid-pump inhibitor anti-ulcer agents, such as omeprazole; (73)
H.sub.2 -blocker anti-ulcer agents, such as cimetidine, famotidine,
nizatidine, and ranitidine; (74) digestants, such as pancrelipase;
(75) prokinetic agents, such as erythromycin; (76) opiate agonist
intravenous anesthetics such as fentanyl; (77) hematopoietic
antianemia agents, such as erythropoietin, filgrastim (G-CSF), and
sargramostim (GM-CSF); (78) coagulation agents, such as
antihemophilic factors 1-10 (AHF 1-10); (79) anticoagulants, such
as warfarin; (80) thrombolytic enzyme coagulation agents, such as
alteplase, anistreplase, streptokinase and urokinase; (81) hormones
and hormone modifiers, such as bromocriptine; (82) abortifacients,
such as methotrexate; (83) antidiabetic agents, such as insulin;
(84) oral contraceptives, such as estrogen and progestin; (85)
progestin contraceptives, such as levonorgestrel and norgestrel;
(86) estrogens such as conjugated estrogens, diethylstilbestrol
(DES), estrogen (estradiol, estrone, and estropipate); (87)
fertility agents, such as clomiphene, human chorionic gonadotropin
(HCG), and menotropins; (88) parathyroid agents such as calcitonin;
(89) pituitary hormones, such as desmopressin, goserelin, oxytocin,
and vasopressin (ADH); (90) progestins, such as
medroxyprogesterone, norethindrone, and progesterone; (91) thyroid
hormones, such as levothyroxine; (92) immunobiologic agents, such
as interferon beta-1b and interferon gamma-1b; (93)
immunoglobulins, such as immune globulin IM, IMIG, IGIM and immune
globulin IV, IVIG, IGIV; (94) amide local anesthetics, such as
lidocaine; (95) ester local anesthetics, such as benzocaine and
procaine; (96) musculoskeletal corticosteroid anti-inflammatory
agents, such as beclomethasone, betamethasone, cortisone,
dexamethasone, hydrocortisone, and prednisone; (97) musculoskeletal
anti-inflammatory immunosuppressives, such as azathioprine,
cyclophosphamide, and methotrexate; (98) musculoskeletal
nonsteroidal anti-inflammatory drugs (NSAIDs), such as diclofenac,
ibuprofen, ketoprofen, ketorlac, and naproxen; (99) skeletal muscle
relaxants, such as baclofen, cyclobenzaprine, and diazepam; (100)
reverse neuromuscular blocker skeletal muscle relaxants, such as
pyridostigmine; (101) neurological agents, such as nimodipine,
riluzole, tacrine and ticlopidine; (102) anticonvulsants, such as
carbamazepine, gabapentin, lamotrigine, phenytoin, and valproic
acid; (103) barbiturate anticonvulsants, such as phenobarbital and
primidone; (104) benzodiazepine anticonvulsants, such as
clonazepam, diazepam, and lorazepam; (105) anti-parkinsonian
agents, such as bromocriptine, levodopa, carbidopa, and pergolide;
(106) anti-vertigo agents, such as meclizine; (107) opiate
agonists, such as codeine, fentanyl, hydromorphone, methadone, and
morphine; (108) opiate antagonists, such as naloxone; (109)
.beta.-blocker anti-glaucoma agents, such as timolol; (110) miotic
anti-glaucoma agents, such as pilocarpine; (111) ophthalmic
aminoglycoside anti-infectives, such as gentamicin, neomycin, and
tobramycin; (112) ophthalmic quinolone anti-infectives, such as
ciprofloxacin, norfloxacin, and ofloxacin; (113) ophthalmic
corticosteroid anti-inflammatory agents, such as dexamethasone and
prednisolone; (114) ophthalmic nonsteroidal anti-inflammatory drugs
(NSAIDs), such as diclofenac; (115) antipsychotics, such as
clozapine, haloperidol, and risperidone; (116) benzodiazepine
anxiolytics, sedatives and hypnotics, such as clonazepam, diazepam,
lorazepam, oxazepam, and prazepam; (117) psychostimulants, such as
methylphenidate and pemoline; (118) antitussives, such as codeine;
(119) bronchodilators, such as theophylline; (120) adrenergic
agonist bronchodilators, such as albuterol; (121) respiratory
corticosteroid anti-inflammatory agents, such as dexamethasone;
(122) antidotes, such as flumazenil and naloxone; (123) heavy metal
antagonists/chelating agents, such as penicillamine; (124)
deterrent substance abuse agents, such as disulfiram, naltrexone,
and nicotine; (125) withdrawal substance abuse agents, such as
bromocriptine; (126) minerals, such as iron, calcium, and
magnesium; (127) vitamin B compounds, such as cyanocobalamin
(vitamin B.sub.12) and niacin (vitamin B.sub.3); (128) vitamin C
compounds, such as ascorbic acid; and (129) vitamin D compounds,
such as calcitriol.
In addition to the foregoing, the following less common drugs may
also be used: chlorhexidine; estradiol cypionate in oil; estradiol
valerate in oil; flurbiprofen; flurbiprofen sodium; ivermectin;
levodopa; nafarelin; and somatropin.
Further, the following new drugs may also be used: recombinant
beta-glucan; bovine immunoglobulin concentrate; bovine superoxide
dismutase; the formulation comprising fluorouracil, epinephrine,
and bovine collagen; recombinant hirudin (r-Hir), HIV-1 immunogen;
human anti-TAC antibody; recombinant human growth hormone (r-hGH);
recombinant human hemoglobin (r-Hb); recombinant human mecasermin
(r-IGF-1); recombinant interferon beta-1a; lenograstim (G-CSF);
olanzapine; recombinant thyroid stimulating hormone (r-TSH); and
topotecan.
Further still, the following intravenous products may be used:
acyclovir sodium; aldesleukin; atenolol; bleomycin sulfate, human
calcitonin; salmon calcitonin; carboplatin; carmustine;
dactinomycin, daunorubicin HCl; docetaxel; doxorubicin HCl; epoetin
alfa; etoposide (VP-16); fluorouracil (5-FU); ganciclovir sodium;
gentamicin sulfate; interferon alfa; leuprolide acetate; meperidine
HCl; methadone HCl; methotrexate sodium; paclitaxel; ranitidine
HCl; vinblastin sulfate; and zidovudine (AZT).
Still further, the following listing of peptides, proteins, and
other large molecules may also be used, such as interleukins 1
through 18, including mutants and analogues; interferons a,
.alpha., .beta., and .gamma.; luteinizing hormone releasing hormone
(LHRH) and analogues, gonadotropin releasing hormone (GnRH),
transforming growth factor-.beta. (TGF-.beta.); fibroblast growth
factor (FGF); tumor necrosis factor-.alpha. & .beta.
(TNF-.alpha.& .beta.); nerve growth factor (NGF); growth
hormone releasing factor (GHRF); epidermal growth factor (EGF);
fibroblast growth factor homologous factor (FGFHF); hepatocyte
growth factor (HGF); insulin growth factor (IGF); invasion
inhibiting factor-2 (IIF-2); bone morphogenetic proteins 1-7 (BMP
1-7); somatostatin; thymosin-.alpha.-1; .gamma.-globulin;
superoxide dismutase (SOD); and complement factors.
Alternatively, the biologically active substance may be a
radiosensitizer, such as metoclopramide, sensamide or neusensamide
(manufactured by Oxigene); profiromycin (made by Vion); RSR13 (made
by Allos); Thymitaq (made by Agouron), etanidazole or lobenguane
(manufactured by Nycomed); gadolinium texaphrin (made by
Pharmacyclics); BuDR/Broxine (made by NeoPharm); IPdR (made by
Sparta); CR2412 (made by Cell Therapeutic); LlX (made by Terrapin);
or the like.
In a particularly preferred embodiment, the biologically active
substance is a therapeutic drug or pro-drug, most preferably a drug
selected from the group consisting of chemotherapeutic agents and
other anti-neoplastics, antibiotics, anti-virals, anti-fungals,
anti-inflammatories, and anticoagulants. Most preferably, the
biologically active substance is paclitaxel.
The biologically active substances are used in amounts that are
therapeutically effective. While the effective amount of a
biologically active substance will depend on the particular
material being used, amounts of the biologically active substance
from about 1% to about 65% have been easily incorporated into the
present delivery systems while achieving controlled release. Lesser
amounts may be used to achieve efficacious levels of treatment for
certain biologically active substances.
Pharmaceutically acceptable carriers may be prepared from a wide
range of materials. Without being limited thereto, such materials
include diluents, binders and adhesives, lubricants, disintegrants,
colorants, bulking agents, flavorings, sweeteners and miscellaneous
materials such as buffers and adsorbents in order to prepare a
particular medicated composition.
Implants and Delivery Systems Designed for Iniection
In its simplest form, a biodegradable therapeutic agent delivery
system consists of a dispersion of the therapeutic agent in a
polymer matrix. The therapeutic agent is typically released as the
polymeric matrix biodegrades in vivo into soluble products that can
be excreted from the body.
In a particularly preferred embodiment, an article is used for
implantation, injection, or otherwise placed totally or partially
within the body, the article comprising the biodegradable polymer
composition of the invention. The biologically active substance of
the composition and the polymer of the invention may form a
homogeneous matrix, or the biologically active substance may be
encapsulated in some way within the polymer. For example, the
biologically active substance may be first encapsulated in a
microsphere and then combined with the polymer in such a way that
at least a portion of the microsphere structure is maintained.
Alternatively, the biologically active substance may be
sufficiently immiscible in the polymer of the invention that it is
dispersed as small droplets, rather than being dissolved, in the
polymer. Either form is acceptable, but it is preferred that,
regardless of the homogeneity of the composition, the release rate
of the biologically active substance in vivo remain controlled, at
least partially as a function of hydrolysis of the phosphoester
bond of the polymer upon biodegradation.
In a preferred embodiment, the article of the invention is designed
for implantation or injection into the body of an animal. It is
particularly important that such an article result in minimal
tissue irritation when implanted or injected into vasculated
tissue.
As a structural medical device, the polymer compositions of the
invention provide a physical form having specific chemical,
physical, and mechanical properties sufficient for the application
and a composition that degrades in vivo into non-toxic residues.
Typical structural medical articles include such implants as
orthopedic fixation devices, ventricular shunts, laminates for
degradable fabric, drug-carriers, biosorbable sutures, burn
dressings, coatings to be placed on other implant devices, and the
like.
In orthopedic articles, the composition of the invention may be
useful for repairing bone and connective tissue injuries. For
example, a biodegradable porous material can be loaded with bone
morphogenetic proteins to form a bone graft useful for even large
segmental defects. In vascular graft applications, a biodegradable
material in the form of woven fabric can be used to promote tissue
ingrowth. The polymer composition of the invention may be used as a
temporary barrier for preventing tissue adhesion, e.g., following
abdominal surgery.
On the other hand, in nerve regeneration articles, the presence of
a biodegradable supporting matrix can be used to facilitate cell
adhesion and proliferation. When the polymer composition is
fabricated as a tube for nerve generation, for example, the tubular
article can also serve as a geometric guide for axonal elongation
in the direction of functional recovery.
As a drug delivery device, the polymer compositions of the
invention provide a polymeric matrix capable of sequestering a
biologically active substance and provide predictable, controlled
delivery of the substance. The polymeric matrix then degrades to
non-toxic residues.
Biodegradable medical implant devices and drug delivery products
can be prepared in several ways. The polymer can be melt processed
using conventional extrusion or injection molding techniques, or
these products can be prepared by dissolving in an appropriate
solvent, followed by formation of the device, and subsequent
removal of the solvent by evaporation or extraction.
Once a medical implant article is in place, it should remain in at
least partial contact with a biological fluid, such as blood,
internal organ secretions, mucous membranes, cerebrospinal fluid
and the like.
EXAMPLES
Example 1
Synthesis of Poly(L-lactide-co-ethyl-phosphate)(Poly(LAEG-EOP))
##STR15##
20 g (0.139 mole of (3S)-cis-3,6-dimethyl-1,4-dioane-2,5-dione
(L-lactide) (obtained from Aldrich Chemical Company, recrystallized
with ethyl acetate, sublimed, and recrystallized with ethyl acetate
again) and 0.432 g (6.94 mmole) of ethylene glycol (99.8%,
anhydrous, from Aldrich) were placed in a 250 mL round-bottomed
flask flushed with dried argon. The flask was closed under vacuum
and placed in an oven heated to 140.degree. C. The flask was kept
at this temperature for about 48 hours with occasional shaking.
The flask was then filled with dried argon and placed in oil bath
heated to 135.degree. C. Under an argon stream, 1.13 g of ethyl
phosphorodichloridate was added with stirring. After one hour of
stirring, a low vacuum (about 20mm Hg) was applied to the system,
and it was allowed to stand overnight. One hour before work-up, a
high vacuum was applied. After cooling, the polymer was dissolved
in 200 mL of chloroform and quenched into one liter of ether twice
to an off-white precipitate, which was dried under vacuum.
It was confirmed by NMR spectroscopy that the polymer obtained was
the desired product, poly(L-lactide-co-ethyl-phosphate)
[P(LAEG-EOP)], as shown in FIGS. 6 and 7.
Example 2
Properties of P(LAEG-EOP)
A P(LAEG-EOP) polymer where (x or y)/n=10:1 was prepared as
described above in Example 1. The resulting
poly(phosphoester-co-ester) polymer was analyzed by GPC using
polystyrene as a standard, and the resulting graph established an
Mw of 33,000 and an Mn of 4800, as shown in FIG. 7.
The viscosity was measured in chloroform (CH.sub.3 Cl) at
40.degree. C. and determined to be 0.315 dL/g. The polymer was
soluble in ethyl acetate, acetone, acetonitrile, chloroform,
dichloromethane, tetrahydrofuran, N-methylpyrrolidone,
dimethylformamide, and dimethyl sulfoxide. The polymer formed a
brittle film, and the Tg was determined by DSC to be 51.5.degree.
C., as shown in FIGS. 2A and 2B.
Example 3
Synthesis of Poly(L-lactide-co-hexyl-phosphate)
[Poly(LAEG-HOP)]
A second poly(L-lactide-phosphate) having the following structure:
##STR16## was also prepared by the method described in Example 1,
except that hexyl phosphorodichloridate ("HOP") was substituted for
EOP (ethyl phosphorodichloridate).
Example 4
Properties of P(LAEG-EOP) and P(LAEG-HOP)
The weight-average molecular weight (Mw) of the
phosphoester-co-ester polymer of Example 1, P(LAEG-EOP), and the
polymer of Example 3, P(LAEG-HOP), were first determined by gel
permeation chromatography (GPC) with polystyrene as the calibration
standard, as shown in FIG. 1. Samples of each were then allowed to
remain exposed to room temperature air to test for ambient,
unprotected storage capability. After one month, the Mw was again
determined for each polymer. The results (plotted in FIG. 5) showed
that, while the Mw for p(LAEG-EOP) was reduced by about one-third
after a month of unprotected ambient conditions, the Mw for
p(LAEG-HOP) remained fairly constant, even showing a slight
increase. See also FIG. 8.
Discs for degradation studies were then fabricated from each
polymer by compression molding at 50.degree. C. and a pressure of
200 MPa. The discs were 4 mm in diameter, 1.5 mm in thickness, and
40 mg in weight. The degradation studies were conducted by placing
the discs in 4 mL of 0.1M PBS (pH 7.4) at 37.degree. C. Duplicate
samples were removed at different time points up to eight days,
washed with distilled water, and dried under vacuum overnight.
Samples were analyzed for weight loss and molecular weight change
(GPC), and the results are shown in FIGS. 4A, 4B, 10A and 10B. Both
polymers, P(LAEG-EOP) and P(LAEG-HOP), demonstrated favorable
degradation profiles.
Example 5
In vivo Biocompatibility of P(LAEG-EOP)
A 100 mg polymer wafer was formed from P(LAEG-EOP) and, as a
reference, a copolymer of lactic and glycolic acid ["PLGA (RG755)"]
known to be biocompatible. These wafers were inserted between
muscle layers of the right limb of adult SPF Sprague-Dawley rats
under anesthesia. The wafers were retrieved at specific times, and
the surrounding tissues were prepared for histopathological
analysis by a certified pathologist using the following
scoring:
______________________________________ Score Level of Irritation
______________________________________ 0 No Irritation 0-200 Slight
Irritation 200-400 Mild Irritation 400-600 Moderate Irritation More
than 600 Severe Irritation
______________________________________
The results of the histopathological analysis are shown below in
Table 8.
TABLE 8 ______________________________________ Inflammatory
Response at Site of Implantation (i.m.) Polymer 3 Days 7 Days 14
Days 1 Month 2 Mos. 3 Mos. ______________________________________
P(LAEG- 130 123 180 198 106 99 EOP) PLGA 148 98 137 105 94 43
(RG755) ______________________________________
See also FIG. 12. The phosphoester copolymer P(LAEG-EOP) was shown
to have an acceptable biocompatability similar to that exhibited by
the PLGA reference wafer.
Example 6
Preparation of Microspheres
Microspheres were made from P(LAEG-EOP) by a solvent evaporation
(double emulsion) method using methylene chloride as a solvent. The
results are shown in FIG. 3.
Example 7
Preparation of Copolymer Microspheres Containing FITC-BSA with 10%
Theoretical Loading Level
One hundred mL of FITC-BSA solution (100 mg/mL dissolved in water)
was added to a solution of 100 mg of P(LAEG-EOP) in 1 mL of
methylene chloride, and emulsified via sonication for 15 seconds on
ice. The resulting emulsion was immediately poured into 5 mL of
vortexing a 1% solution of polyvinyl alcohol (PVA) in 5% NaCl, and
vortexing was maintained for one minute. The emulsion thus formed
was then poured into 20 mL of a 0.3% PVA solution in 5% NaCl, which
was being stirred vigorously. Twenty five mL of a 2% solution of
isopropanol was added, and the mixture was kept stirring for one
hour to ensure complete extraction. The resulting microspheres were
collected via centrifugation at 3000.times.g, washed 3 times with
water, and freeze dried.
Different formulations of microspheres were made by using as the
second aqueous phase a 5% NaCl solution or a 5% NaCl solution also
containing 1% PEG 8000. Yet another technique was used in
evaporating the solvent by stirring the mixture overnight, thus
forming microspheres by solvent evaporation.
Example 8
Estimation of Encapsulation Efficiency and Loading Level
The loading level of FITC-BSA was determined by assaying for FITC
after hydrolyzing the microspheres with 0.5 N NaOH overnight. The
amount of FITC-BSA was compared with a standard curve that had been
generated by making a series of FITC-BSA solutions in 0.5 N NaOH.
The encapsulation efficiency of the microspheres was determined by
comparing the quantity of FITC-BSA entrapped with the initial
amount in solution via fluorometry. The encapsulation efficiency
(%) and loading level (%) of FITC-BSA are shown in Table 1
below.
TABLE 1 ______________________________________ Encapsulation
Efficiency and Loading Level of FITC-BSA High Low Loading Loading
Loading (%) (24.98%) (1.5%) ______________________________________
Encapsulation Efficiency (%) 98.10 91.70
______________________________________
Example 9
Cytotoxicitv of the Copolymer
Microspheres containing P(LAEG-EOP) were added to 96-well tissue
culture plates at different concentrations. Human gastric carcinoma
cells (GT3TKB) were then seeded at a rate of 10.sup.4 cells/well.
The cells were then incubated with the microspheres in the wells
for 48 hours at 37.degree. C. The cell proliferation rate was
analyzed by MTT assay, and the results were plotted as % relative
growth vs. concentration of copolymer microspheres in the tissue
culture well, as shown in FIG. 9.
Example 10
Effect of Fabrication Method on the Release of FITC-BSA from
Microspheres
Fifty mg of microspheres of a polymer of the invention were
suspended in vials containing 10 mL of PBS, and the vials were
shaken in an incubator at 37.degree. C. and at a rate of 220 rpm.
The supernatant fluid was replaced at various time points, and the
amount of FITC-BSA released was analyzed by spectrophotometry at
492 nm. The results were plotted as % cumulative release of
FITC-BSA from the microspheres vs. time in hours, as shown in FIG.
13.
Example 11
Preparation of P(LAEG-EOP) Microspheres Containing Lidocaine Using
Polyvinyl Alcohol as the Non-Solvent Phase
A solution of 0.5% w/v polyvinyl alcohol (PVA) in deionized water
solution was prepared in a 600 mL beaker by combining 1.05 g of PVA
with 210 mL of deionized water. The solution was stirred for one
hour and filtered. A polymer/drug solution was prepared by
combining 630 mg of polymer and 70 mg of lidocaine in 7 mL of
methylene chloride and mixing by vortex. The PVA solution was mixed
at 500 rpm with an overhead mixer, and the polymer/drug solution
was added dropwise. After 30 minutes of mixing, 200 mL of cold
deionized water was added to the stirring PVA solution. The
resulting mixture was stirred for a total of 3.5 hours. The
microspheres formed were filtered off, washed with deionized water,
and lyophilized overnight.
Microspheres loaded with 4.2% w/w lidocaine were thus obtained.
Approximately 10 mg of microspheres were placed in a phosphate
buffer saline (0.1M, pH 7.4) at 37.degree. C. on a shaker and
sampled regularly. The results were plotted as % lidocaine released
vs. time in days, as shown in FIG. 16.
Example 12
Preparation of P(DAEG-EOP)
The d,l racemic mixture of poly(L-lactide-co-ethyl-phosphate)
["P(DAEG-EOP)"], was prepared in the same manner as P(LAEG-EOP), as
described in Example 1.
Example 13
Preparation of P(DAEG-EOP) Microspheres With Lidocaine Using
Silicon Oil as the Non-solvent Phase
Two percent sorbitan-trioleate, which is commercially available
from Aldrich under the tradename Span-85, in silicon oil was
prepared in a 400 mL beaker by combining 3 mL of Span-85 with 150
mL of silicone oil and mixing with an overhead stirrer set at 500
rpm. A P(DAEG-EOP) polymer/drug solution was prepared by dissolving
400 mg of the polymer prepared above in Example 9, and 100 mg of
lidocaine in 4.5 mL of methylene chloride. The resulting
polymer/drug solution was added dropwise to the silicone oil/span
mixture with stirring. The mixture was stirred for an hour and 15
minutes. The microspheres thus formed were filtered off and washed
with petroleum ether to remove the silicone oil/span mixture, and
lyophilized overnight.
450 mg of microspheres loaded with 7.6% w/w lidocaine were thus
obtained. Approximately 10 mg of microspheres were placed in
phosphate buffer saline (0.1M, pH 7.4) at 37.degree. C. on a shaker
and sampled regularly. The results were plotted as % lidocaine
released vs. time in days, as shown in FIG. 17.
Example 14
Biocompatibility of Poly(phosphoester) Microspheres in Mouse
Peritoneal Cavity
The biocompatibility of biodegradable poly(phosphoester)
microspheres of the invention was tested as follows:
Three 30 mg/mL samples of lyophilized
poly(L-lactide-co-ethyl-phosphate) microspheres were prepared, the
first having diameters greater than 75 microns, the second having
diameters within the range of 75-125 microns, and the third having
diameters within the range of 125-250 microns. Each sample was
injected intra-peritoneally into a group of 18 female CD-1 mice
having a starting body weight of 25 g. Animals in each group were
weighed, sacrificed, and necropsied at 2, 7 and 14 days, and at 1,
2 and 3 months. Any lesions detected during the necropsy were
graded on a scale of 0 to 4, with 0 indicating no response to
treatment and 4 indicating a severe response to treatment.
Inflammatory lesions were observed to be restricted to an
association with the microspheres on peritoneal surfaces or within
fat tissue, and were compatible with foreign body isolation and
encapsulation. Focal to multifocal supportive peritoneal steatitis
with mesothelial hyperplasia was observed at 2-7 days, but
gradually resolved by macrophage infiltration, the formation of
inflammatory giant cells, and fibrous encapsulation of the
microspheres at later sacrifices. Occasional adherence of
microspheres to the liver and diaphragm, with associated
inflammatory reaction, was also seen. Lesions related to
microspheres were not seen within abdominal or thoracic organs.
Microspheres, which were detected throughout the duration of the
study, appeared transparent at early sacrifices but, at later
times, developed crystalline material internally. No effects on
body growth were observed. The peritoneal reaction was observed to
be limited to areas directly adjacent to the microspheres with no
apparent deleterious effects on major thoracic or abdominal
organs.
The invention being thus described, it will be obvious that the
same may be varied in many ways. Such variations are not to be
regarded as a departure from the spirit and scope of the invention
and all such modifications are intended to be included within the
scope of the following claims.
* * * * *